UA64792C2 - Pyrrole [2,3-d]pyrimidine derivatives, a pharmaceutical composition (variants), a method for inhibition of protein tyrosine kinase or janus kinase 3 of mammals (variants) and a method for treatment (variants) - Google Patents

Abstract

A compound of formula (I) wherein R1, R2 and R3 are as denned in the description, and are inhibitors of the enzyme protein tyrosine kinases such as Janus Kinase (3) and as such are useful therapy as immunosuppressive agents for organ transplants, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis. Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, Leukemia and other autoimmune diseases. , (?)

Description

The presented invention relates to pyrrolo|2,3-CHypyrimidine derivatives, which are inhibitors of protein tyrosine kinase, such as the enzyme Janus kinase Z (dapib5 Kypase 3) (hereinafter referred to as ЧАКЗ), used in therapy: as immunosuppressive agents for transplanted organs, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications caused by diabetes, cancer, asthma, atonic dermatitis, autoimmune thyroid diseases, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other conditions in which immunosuppression is desirable.

This invention also relates to a method of using such compounds in the treatment of the above-mentioned conditions in mammals, especially humans, and pharmaceutical compositions used therein.

UAKZ is a member of the Janus family of protein tyrosine kinases. Although other members of this family are expressed in essentially all tissues, the expression of AKZ is restricted to hematopoietic cells. This is consistent with its essential role in signaling through receptors 11-2, I/-4, 11-7, 11-9 and I/ -15 due to the non-covalent association of UACZ with the gamma chain, in general, with its multichain receptors. Populations of X5CIO patients have been identified by strictly reduced levels of the CACZ protein or with genetic defects in the normal gamma chain, suggesting that immunosuppression must be due to blocking the passage of the signal along the "ACZ way Animal studies have shown that AACZ not only plays a crucial role in the maturation of B and T lymphocytes, but also that AACZ is very necessary in maintaining the functioning of T cells. Modulation of immune activity through these novel mechanisms can be demonstrated in the treatment of diseases caused by T cell proliferation, such as transplant rejection and autoimmune diseases.

Summary of the invention

The presented invention relates to a compound of the formula:

In in?

M or its pharmaceutically acceptable salt; in which B' is a group of the formula: c? r 4

Ah in (SN), still vyakiyuey1 or 2;

A" is selected from the group containing hydrogen, (Ci1-Cv)alkyl, (Co-Cv)alkenyl, (C2-Cv)alkynyl, where alkyl, alkenyl and alkynyl groups are optionally substituted with deuterium, hydroxy, amino, trifluoromethyl, (C1-

Ca) alkoxy, (Ci-Cv) acyloxy, (C1-Cv) alkylamino, ((C1i-Cv) alkyl) gamino, cyano, nitro, (Co-Cv) alkenyl, (C2-

C)alkynyl or (C1i-C)acylamino; or B" is (C3-C10)cycloalkyl, where the cycloalkyl group is optionally

Substituted by deuterium, hydroxy, amino, trifluoromethyl, (C1-Cv)acyloxy, (C1-Cv)acylamino, (C1-Cv)alkylamino, ((Ci-Cv)alkyl)gamino, cyano, cyano(C1-Cv)alkyl, trifluoromethyl (Ci-Ci)alkyl, nitro, nitro(Ci-Ci)alkyl or (Ci-Ci)acylamino;

AND? is selected from the group consisting of trifluoromethyl(C1-C8)alkyl, (C1-C3)alkyldifluoromethylene)(C1-C3)alkyl, (C3-C8)cycloalkyl, where the cycloalkyl group is optionally substituted from one to five carboxy, cyano, amino, deuterium, hydroxy, (C1-Cv)alkyl, (C1i1-Cv)alkoxy, halogen, (C1-Cv)acyl, (C1-Cv)alkylamino, amino(C1-Cv)alkyl, (Cch -

Св)Alkoxy-СО-МН, (Си-Св)alkylamino-СО-, (С2-Св)alkenyl, (С2-Св)alkynyl, (С1-Св)alkylamino, amino(С1и-Св)alkyl, hydroxy(С -Cv)alkyl, (C1-Cv)alkyl(C1i-Cv)alkyl, (C1-Cv)acyloxy(Ci-Cv)alkyl, nitro, cyano(Ci-Cv)alkyl, halogen(C1i-Cv)alkyl, nitro (Ci-Cv)alkyl, trifluoromethyl, trifluoromethyl (Ci-Cv)alkyl, (C1i-Cv)acylamino, (Ci1-

C1-Cv)acylamino(C1-Cv)alkyl, (C1-Cv)alkyl(C1-Cv)acylamino, amino(C1i-Cv)acyl, amino(C1-Cv)acyl(Ci-Cv)alkyl, (C1i1-Cv) alkylamino(Ci-Cv)acyl, (C1-Ci)alkyl)gamino(Ci-Ci)acyl,

Sv)alkyl-Z(O)t, V'YAVTYAM5(O) t, V'VYAMO(O)t(Si-Cv)alkyl, VZB(O)tAYAM, VZ5(O) tA M (Si-Sv )alkyl, where t is 0,1 or 2 and B!5 and B!E are each independently selected from hydrogen or (C1i-Cv)alkyl; or B? is (C3-Cio)cycloalkyl(C1-

C1-C8) alkyl, (C1-C8) acyloxy (C1-C8) alkyl, (C2-C8) alkoxy (C1-C8) alkyl, piperazinyl (C1-C8) alkyl, (C1-C8)

C1-acylamino(C1-C8) alkyl, (C1-C8) daryl(C1-C8) alkoxy(C1-C8) alkyl, (C5-Ce) heteroaryl(C1-C8) alkoxy(C1-

Cl)alkyl, (C1i-Cv)alkylthio(C1i-Cv)alkyl, (Cv-Cio)darylthio(C1-Cv)alkyl, (Ci-Cv)alkylsulfinyl(C1-Cv)alkyl, (Cv-Cio)darylsulfinyl( C1-Cv)alkyl, (C1i-Cv)alkylsulfonyl(Ci-Cv)alkyl, (Cv-Cio))darylsulfonyl(Ci-

C1-Cv)alkyl, amino(C1-Cv)alkyl, (C1-Cv)alkylamino(Ci-Cv)alkyl, ((C1-Cv)alkyl)gamino, (Ci-Cv)alkyl, (Ce2-

Св)alkenyl, (С2-Св)alkynyl, where allyl, alkenyl and alkynyl groups are optionally substituted from one to five cyano, nitro, halogen, deuterium, hydroxy, carboxy, (С1-Св)acylamino, ( C1-Cv) alkoxy(C1-Cv) acylamino, amino(C1i-Cv) acyl, (Ci-Cv) alkylamino(Ci-Cv) dacyl or ((C1i-Cv) alkyl) gamino(Ci-Cv) acyl; or B? is VZSO (C1-

C1)alkyl or B'ZCO(C3-C0)cycloalkyl, where BZ is B?OO or B2OB2!M, where BO and B?! each independently selected groups containing hydrogen, deuterium, (Ci-Cv)alkyl, (Cv-CiO)aryl(Ci-Cv)alkyl or (Cv-

Co)heteroaryl(Ci-Cv)alkyl; or B? is B", B'C1-C1)alkyl or B'(C3-C10)cycloalkyl, where B" is (Se-

Ce)heterocycloalkyl, (C1i-Cv)dacylpiperazine, (Cv-Cio)darylpiperazine, (C5-Ce)heteroarylpiperazine, (Cch1-

Cn)alkylpiperazine, (Cn-C1io)daryl(C1-Cn)alkylpiperazine, (C5-Ce)heteroaryl(Ci-Cn)alkylpiperazine, morpholine, thiomorpholine, piperidine, pyrrolidine, liperidyl, (Ci-Cn)alkylpiperidinyl, (Cn-

Cio)darylpiperidyl, (C5-Ce)heteroarylpiperidyl, (Ce-Cio)daryl(C,Cb)alkylpiperidyl, (Cv5-

Co)heteroaryl(C1-C8)alkylpiperidyl or (C1-C8)acylpiperidyl; or B? is a group of the formula:

(sleep), any value is 0, 1 or 2; heh, 1, 2 or 3; or B? is a group of the formula:

ЮК, (Е) ИИ (Р), in which 9, Й and | each, independently, takes values from 0 to 3;

E, Ki P each, independently, oxygen, 5(O)a, where there is 0, 1 or 2, MAE or SV"B8;

VAZ is selected from the group containing hydrogen, (C1-Cv)alkyl, trifluoromethyl, trifluoromethyl(Ci-Cv)alkyl, (C1-

C1-C3 alkyldifluoromethylene), (C1-C3 alkyldifluoromethylene) C-C3) alkyl, (C-C) alkoxy(C-C) acyl, /(C-

C)alkylamino(Ci-Cv)acyl, ((C1i-Cv)alkyl)gamino(Ci-Cv)acyl, (Ce-CiO)aryl, (C5-Ce)heteroaryl, (Ci-Ciodo)daryl (Ci1-

Cl)alkyl, (C5-Ce)heteroaryl(C1-Cv)alkyl, (Ce-Siodaryl(Cv-Cio)daryl, (Ce-Sidaryl(Cv-Cio)daryl(Ci-Cv)alkyl, (Cz-

Cl)cycloalkyl, /(C3-Cv)cycloalkyl(Ci-Cv)alkyl, hydroxy(Co-Cv)alkyl, (Ci-Cv)acyloxy(Co-Cv)alkyl, / (Cch1-

C1-C2-C8-alkyl, piperazinyl (C1-C8) alkyl, (C1-C8) acylamino(C1-C8) alkyl. (C1-C1io)daryl(C1-C1)alkyl(C1-

C1-C6)alkyl, (C5-C6)heteroaryl(C1-C6)alkyl (C1-C6)alkyl, (C1-C6)alkylthio(C1-C6)alkyl, (C1-C6)arylthio(C1-C6)alkyl, ( C1-Cv)alkylsulfinyl(Ci-Cv)alkyl, (Cv-Cv)darylsulfinyl(Ci-Cv)alkyl, (C1-Cv)alkylsulfonyl(C1i-Cv)alkyl, (Cv-

Cio)darylsulfonyl(Ci-Cv)alkyl, amino(Ci-Cv)alkyl, (Ci-Cv)alkylamino(Ci-Cv)allyl, ((C1-Cv)alkyl)gamino(C1-

C1-C1-alkyl, C1-C1-C1 alkyl, where BZ is B?OO or B2OB2M, where 829 and B! each independently selected from the group consisting of hydrogen, (C1-C8)alkyl, (C1-C8)daryl(C1-C8)alkyl or (C5-Ce)heteroaryl(C1-C8)apgal; or B'Y(C2-C8)alkyl, where Bb is (C1-C8)acylpiperazine, (C8-C8)arylpiperazine, (C5-C8)heteroarylpiperazine, /(C1-

Cn)alkylpiperazine, (Cn-C1io)daryl(C1-Cn)alkylpiperazine, (C5-Ce)heteroaryl(Ci-Cn)alkylpiperazine) morpholine, thiomorpholine, piperidine, pyrrolidine, piperidyl, (Ci1i-Cn)alkylpiperidyl, (Cn-

Cio)darylpiperidyl, (C5-Ce)heteroarylpiperidyl, (Cv-C0)daryl(C1-Cv)alkylpiperidyl, (Cv-

Ce)heteroaryl(C1-Cv)alkylpiperidyl, (C1i-Cv)alkoxyacyl, (C1-Cv)alkylaminoaryl, (C-

C)alkyl)gaminoacyl or (C1i-C)acylpiperidyl;

A" and BZ are each, independently, selected from the group containing hydrogen, (Ci-Cv)alkyl, amino, hydroxy, (Cch-

Св)apyukal, (Си1и-Св)alkylamino, ((С1-Св)alkyl)gamino, (С1-Св)acylamino, (С1-Св)acyl(С1и-Св)alkylamino, carboxy, (Си-Св)alkyloxyacyl, (C1-Cv)alkylaminoacyl, (Ci-Cv)alkyl)aminoacyl, aminoacyl, trifluoromethyl, trifluoromethyl (Ci-Cv)alkyl, (C1-Cv)alkyldifluoromethylene), (C1-Cz)alkyldifluoromethylene)(Ci-Cz)alkyl, (St-

Cio)daryl, (C5-Ce)heteroaryl, (Cv-Cio)daryl(Ci-Cv)alkyl, (C5-Ce)heteroaryl(Ci-Cv)alkyl, (Cv-Cio)daryl(Cv-

Sto)aryl, (Cv-Sthio)daryl(Cv-Stodaryl(Ci-Cv)alkyl, (C3-Cv)cycloalkyl, (C3-Cv)cycloalct(C1-Cv)alkyl, hydroxy(C1-

Cl)alkyl, (C1i1-Cv)acyloxy(Ci-Cv)alkyl, (C1-Cv)alkoxy(C1-Cv)alkyl, piperazinyl(Ci-Cv)alkyl, (Ci-

C1-Cv)acylamino(C1-Cv)alkyl, piperidyl, (C1-Cv)alkylpiperidyl, (Cv-Sidaryl(Ci-Cv)alkyl (Ci-Cv)alkyl, (Cv5-

Co)heteroaryl(C1-Cv)alkoxy(C1-Cv)alkyl, (Ci1-Cv)alkylthio(Ci-Cv)alkyl, (Cv-Cio)arylthio(Ci-Cv)alkyl, (Ci-

C1i-Cv) alkylsulfinyl (C1i-Cv) alkyl, (Ci-Ci) darylsulfinyl (Ci-Ci) alkyl, (Ci-Ci) alkylsulfonyl (Ci-Ci) alkyl, (Ci-

Cio)darylsulfonyl(Ci-Cv)alkyl, amino(Ci-Cv)alkyl, (Ci-Cv)alkylamino(Ci-Cv)alkyl, ((C1i-Cv)alkyl)gamino(C1-

C1-alkyl, C1-C1-C1-alkyl or C3-C1-C1-cycloalkyl, where C1-C1-C1-cycloalkyl is B? О or В2ОВ2'М, where ВО and В?! each independently selected from the group consisting of hydrogen, (Ci-Ci)alkyl, (Ci-Ci)aryl(Ci-Ci)alkyl or (Ci-

Se)heteroaryl(Ci-Cv)alkyl; B", B'Y(C1-C1)alkyl or B'Y(C3-C10)MNKpoapKt, where B": is (C1-C1)acylpiperazine, (C1-C10)darylpiperazine, (C5-Ce)heteroarylpiperazine, ( C1i-Cv)alkylpiperazine, (Ce-Cio)daryl (Ci-

C5-C6)alkylpiperazine, (C5-C6)heteroaryl(C1-C6)alkyl piperazine, morpholine, thiomorpholine, piperidine, pyrrolidine, piperidyl, (C1-C6)alkylpiperidyl, (C5-C6)darylpiperidyl, (C5-C6)heteroarylpiperidyl, ( C1-C8)daryl(C1-C8)alkylpiperidyl, (C5-C8)heteroaryl(C1-C8)alkylpiperidyl or (C1-C8)acylpiperidyl; or groups of the formula: (o) wherein B is 0, 1, 2 or 3; and 7 is hydroxy, (C 1 -C 6 ) alkoxy or MVA'B?, where B! and B? are each independently selected from the group , containing hydrogen, (Ci-Ci)alkyl, piperidyl, (Ci-Ci)alkylpiperidyl, (Ci-Ci)darylpiperidyl, (C5-Ci)heteroarylpiperidyl, (Ci-Ci)daryl(Ci-Ci)apkylpiperidyl, (C5 -Ce)heteroaryl(Ci-Cv)alkylpiperidyl, (Ci-Cv)dacylpiperidyl, (Cv-

Cio)daryl, (C5-Ce)heteroaryl, (Cv-Cio)daryl(Ci-Cv)alkyl, (C5-Ce)heteroaryl(Ci-Cv)alkyl, (Cv-Cio)daryl(Cv-

Cio)aryl, (Cev-Cio)aryl(Cv-Cio)aryl(Ci-Cv)alkyl, (C3-Cv)cycloalkyl, (C3-Cv)cycloalkyl(Ci-Cv)alkyl, A5(C1-

C1-C8 alkyl, (C1-C8) alkyl(SNEZ)(C1-C8) alkyl, where B? are hydroxy, (C1-Cv)acyloxy, (C1i-Cv)alkoxy, piperazine, (C1-

Cy)acylamino, (Ci-Ci)alkylthio, (Ci-Ci)arylthio, (C1-Ci)alkylsulfinyl, (Ci-Ci)darylsulfinyl, (Cch1-

Cn)alkylsulfoxyl, (Cn-Cn)arylsulfoxyl, amino, (Cn-Cn)alkylamino, ((Cn-Cn)alkyl)gamino, (Cch1-

C)acylpiperazine, (Ci-Ci)alkylpiperazine, (Ci-CiO)aryl(C1i-Ci)alkylpiperazine, (C5-Ce)heteroaryl(Ci-

C)alkylpiperazine, morpholine, thiomorpholine, piperidine or pyrrolidine; Be(Ci-Cv)alkyl, (C1-

Cn)alkyl(CNRU)(Ci-Cn)alkyl, where VU is piperidyl, (Ci-Cn)alkylpiperidyl, (Ce-CiO)darylpiperidyl, (Cn-

Cio)daryl(Ci-Cv)alkylpiperidyl, (C5-Ce)heteroarylpiperidyl or (C5-Ce)heteroaryl(Ci1-

C)alkylpiperidyl; or B' is OB? or 5(0)987, where 0, 1 or 2; and

IN? is selected from the group consisting of trifluoromethyl(Ci-Ci)alkyl, (Ci-Ci)alkyldifluoromethylene)(Ci-Ci)alkyl, (Ci-Ci)cycloalkyl, where the cycloalkyl group is optionally substituted from one to five carboxy, cyano, amino, hydroxy, (Ci-Ci) alkoxy, halogen, (Ci-Ci) alkyl(O)t, where t is 0, 1 or 2; B'V'YAEM(5)t, det is 0, 1 or 2 and B'' and B'E are each, independently, selected from the group containing hydrogen or (C1-C8)alkyl; (С1и-Св)acyl, (С1-Св)alkylamino, amino(Си1-Св)alkyl, (С1-Св)alkyl-СО-МН, (С1-Св)alkylamino-СО-, В5В!94-2О-0 -, B'ZA19M-CO-(Ci-Cv)alkyl, where

VZ and VE are as mentioned above; (C2-Cv)alkenyl, (C2-Cv)alkynyl, (Ci1-Cv)alkylamino, amino(C1-Cv)alkyl, hydroxy(Ci-Cv)alkyl, (C1-Cv)alkyl (C1-Cv)alkyl, (C1i-Cv)acyloxy(Ci-Cv)alkyl nitro, cyano(Ci-Cv)alkyl, nitro(Ci-Cv)alkyl, trifluoromethyl, trifluoromethyl(Ci1-Cv)alkyl, (Ci-Cv)acylamino, (C1- St)Alkoxy(Sch1-

C)acylamino, amino(Ci-Cv)acyl, (Ci-Cv)alkylamino(Ci-Cvdacyl or ((Ci-Cv)alkyl)gamino(Ci-Cv)acyl; (Co-

C1-C8)alkenyl, (C1-C8)alkynyl, (C3-C8)cycloalkyl(C1-C8)alkyl, (C1-C8)acyloxy(C1-C8)alkyl, (C1-C8)alkyl(C1-

C1-C8) alkyl, piperazinyl (C1-C8) alkyl, (C1-C8) acylamino(C1-C8) alkyl, (C1-C8) daryl(C1-C8) alkoxy (C1-C8) alkyl, (C8-

Co)heteroaryl(C1-Cv)alkoxy(C1-Cv)alkyl, (Ci1-Cv)alkylthio(Ci-Cv)alkyl, (Cv-Cio)arylthio(Ci-Cv)alkyl, (Ci-

C1i-Cv) alkylsulfinyl (C1i-Cv) alkyl, (Ci-Ci) darylsulfinyl (Ci-Ci) alkyl, (Ci-Ci) alkylsulfonyl (Ci-Ci) alkyl, (Ci-

Cio)darylsulfonyl(Ci-Cv)alkyl, amino(Ci-Ci-Cv)alkyl, (Ci-Ci)alkylamino(Ci-Ci)alkyl, ((Ci-Ci)alkyl)gamino, (Ci-

C)alkyl, where the alkyl group is optionally substituted by one to five cyano, nitro, hydroxy, carboxy, (Си1-

C1-Cv)acylamino, (C1-Cv)Alkoxy(C1-Cv)acylamino, amino(C1i-Cv)acyl, (Ci1i-Cv)alkylamino(Ci-Cv)dacyl or ((Ci-

C1-C8)alkyl)amino(C1-C8)acyl; В'ЕСО(С1-Св)апКт or ВЗСО(С3-Ско)cycloalkyl, where ВЗ is В?OO or В2ОВ2"M, where В2о and В"! each independently selected from the group consisting of hydrogen, (C1-C8)alkyl, (C1-C8)daryl(C1-C8)alkyl or (C8-

Se)heteroaryl(Ci-Cv)alkyl; ВЯ, BС1-C1)alkyl or B(C3-C0)cycloalkyl, where B" is (C0-C0)heterocycloalkyl, (C1i-C8)acylpiperazine, (C1-C8)darylpiperazine, (C5-Ce)heteroarylpiperazine, ( C1-Cv)alkylpiperazine, (Cv-Cv)daryl(Ci-Cv)alkylpiperazine, (C5-Ce)heteroaryl(C1-Cv)alkylpiperazine, morpholine, thiomorpholine, piperidine, pyrrolidine, piperidyl, (C1i-Cv)alkylpiperidinyl, ( See-Sio)darylpiperidyl, (St-

Ce)heteroarylpiperidyl, (C1-Sidaryl(C1-C1)alkylpiperidyl, (C5-Ce)heteroaryl(C1-C1)alkylpiperidyl or (C1-C1)dacylpiperidyl; or B? is a group of the formula:

Yu, (E) II (R); in which 9, Й and | each, independently, takes values from 0 to 6;

E, K and P are each, independently, oxygen, Z(O)a where 0, 1 or 2, MAE or SV'"VZ, where NE, B" and VZ are as indicated above;

B2 and B3 are each independently selected from the group containing hydrogen, deuterium, amino, halogen, hydroxy, nitro, carboxy, (C2-Cv)alkenyl, (C2-Cv)alkynyl, trifluoromethyl, trifluoromethoxy, (Ci-Cv) alkyl, (Ci-Ci)alkyl, where the alkyl or alkoxyl group is optionally substituted by one to three groups selected from halogen, hydroxy, carboxy, amino(Ci-Ci)alkylthio, (Ci-Ci)alkylamino, ((C1-C)alkyl)gamino, (C5-Ce)heteroaryl, (C2-

Coe)heterocycloalkyl, (C3-Ce)cycloalkyl or (Cn-Cio)aryl; or B: and BZ each, independently, (C3-C10)cycloalkyl, (C3-C10)cycloalkyl, (C1-C1)alkylamino, ((C1-C1)alkyl)ugamino, (C1-C10)darylamino, (C1- St)alkiltio, (St-

C1-C10)arylthio, (C1-C10)alkylsulfinyl, (C1-C10)darylsulfinyl, (C11-C10)alkylsulfonyl, (C1-C10)darylsulfonyl, (C1-

C1-acyl, (C1-C8) alkoxy-CO-MH-, (C1-C8) alkylamino-CO-, (C8-Ce) heteroaryl, (C8-Ce) heterocycloalkyl or (C8-

Cio)aryl, where heteroaryl, heterocycloalkyl, and aryl groups are optionally substituted one to three times by halogen, (Ci-Ci)alkyl, (Ci-Ci)alkyl-FO-MH-, (Ci-Ci)alkyl- CO-MH-, (C1-Cv)alkyl-"CO-MH-(Schi-

C1-Cv)alkyl, (C1-Cv)alkyl-CO-MH-(C1-Cv)allyl, (Ci1-Cv)alkyl-CO-MH-(C1-Cv)alkyl, carboxy, carboxy(C1-Cv)alkyl, carboxy(C1-Cv)alkyloxy, benzyloxycarbonyl(C1-Cv)alkyloxy, (C1-

C1-C8) alkoxycarbonyl(C1-C8) alkoxy, (C1-C8) daryl, amino, amino(C1-C8) alkyl, (C1-C8) alkoxycarbonylamino, (C1-C8) daryl(C1i-C8) alkoxycarbonylamino, (C1-C8) C1i-Cv)alkylamino, ((C1i-Cv)alkyl)gamino, (Ci1i-Cv)alkylamino(Cc-

C1-Cv)alkyl, ((C1-Cv)alkyl)gamino(Ci-Cv)alkyl, hydroxy, (C1-Cv)alkyl, carboxy, carboxy(C1-Cv)alkyl, (C1-

C1-C1-Alkoxycarbonyl, (C1-C1-C1)Alkoxycarbonyl(C1-C1-C1)alksh, (C1-C1-C1)Alkoxy-CO-MH-, (C1-C1-C1)Alkyl-CCO-MH-, cyano, (C5-Ce)Heterocycloalkyl, amino-СО-МН-, (С1-Св)alkylamino-СО-МН-, ((Сч-

Sv)alkyl)ugamino-CO-MH-, (Cv-Cio)darylamino-CO-MH-, (Cv-Ce)heteroarylamino-CO-MH-, (C1-Cv)alkylamino-CO-

NN-(Si-Cv)alkyl, ((C1-Cv)alkyl)gamino-CCO-MH-(Ci-Cv)alktom (Cv-Ci))darylamino-CO-MH-(Ci-Cv)allyl, (Cv) -

Se)heteroarylamino-CO-MH-(C1i-Cv)alkyl, (Ci-Cv)alkylsulfonyl, (C1-Cv)alkylsulfonylamine, /(Ci1-

C1-alkylsulfonylamino(C1-C1)alkyl, (Ce-Cio)darylsulfonyl, (Ce-Cio)darylsulfonylamine, (Cc-

Cio)arylsulfonylamino(Ci1-Cv)alkyl, (C1i1-Cv)alkylsulfonylamino, (C1-Cv)alkylsulfonylamino(Ci1-

C1-alkyl, (C5-Ce)heteroaryl or (C2-Ce)heterocycloalkyl; provided that when one of B? and B? is hydrogen, the other B? or B? cannot be a (St. Sio) gift or (St.

Cio)daryl(C:i-Cv)alkyl; provided that when B" is hydrogen, unsubstituted (Ci-Cv)alkyl or unsubstituted (C3-CiO)cycloalkyl: B? cannot be (Ce-CiO)aryl(Ci-Cv)alkyl; B2O and B"! cannot be (C5-Ce)heteroaryl(C1i-Cv)alkyl; and VE cannot be (Ci-Ci)heterocycloalkyl, morpholine, thiomorpholine, piperidine, pyrrolidine, piperidinyl or (Ci-Ci)alkylpiperidinyl; provided that when zr: and zr alkenyl or alkynyl carbons cannot be replaced by a hydroxy or amino group; provided that when B? is hydrogen, VZ cannot be amino(Ci-Cv)alkyl, (Ci-Cv)alkyl, (Ci-

C1-C8)alylamino(C1-C8)alkyl, ((C1-C8)alkyl)gamino(C1-C8)alkyl, furanyl, (C1-C8)alkoxy(C1-C8)alkyl or carboxy(C1-C8)alkyl; provided that B" and B? cannot simultaneously be hydroxy(Ci-Cv)alkyl; provided that when B" is (Ci-Cv)alkyl, B? cannot be (C1-Cv) alkoxy (C1i-Cv) alkyl or carboxy (Ci1-

C) alkyl; and under the condition that V! cannot be carboxy(C1-C8)alkylthio or (C1-C8)alkylcarbonyl(C1-C8)alkylthio.

The present invention also relates to pharmaceutically acceptable acid-addition salts of compounds of formula I. The acids used in the preparation of pharmaceutically acceptable acid-addition salts of the above-mentioned main compounds of the present invention are those that form non-toxic acid-addition salts, i.e., salts that contain pharmacologically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (ie, 1,1-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

The invention also relates to base-addition salts of formula I. The bases that can be used in the preparation of pharmaceutically acceptable base-addition salts of the above-mentioned compounds of the present invention of an acidic nature are those that form non-toxic base salts with such compounds. Such non-toxic salts include, but are not limited to, derivatives of pharmacologically acceptable cations, such as alkali metal cations (eg, potassium and sodium) and alkaline earth metal cations (eg, calcium and magnesium), ammonium, or water-soluble amino addition salts, such as M-methylglucamine -(meglumine), and lower alkanolammonium and other basic salts of pharmaceutically acceptable organic amines.

The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having a linear, branched or cyclic chain or a combination thereof.

The term "Alkoxy" as used herein includes an -O-alkyl group in which the alkyl is as defined above.

The term "halogen" as used herein, unless otherwise indicated, includes chlorine, fluorine, bromine and iodine.

The compounds of the present invention may contain double bonds. When such bonds are present, the compounds of the invention exist in both cis and trans configurations and as mixtures thereof.

Unless otherwise indicated, the alkyl and alkenyl groups mentioned herein, as well as the alkyl substituent of other groups mentioned herein (e.g., alkoxy), may be linear or branched and may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ) or be linear or branched and contain a cyclic substituent. Unless otherwise specified, halogen includes fluorine, chlorine, bromine, and iodine. (C3-C10)Cycloalkyl, as used herein, refers to cycloalkyl groups containing from zero to two levels of unsaturation, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo( |3.2.1|octane, nonbornanyl, etc. (Cg2-Ce)heterocycloalkyl, when used herein, means pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxyranyl, methylenedioxy, chromenyl, isoxazolidinyl, 1,3-oxazolidine -Z-yl, isothiazolidinyl, 1,3-thiazolidin-Z-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl .

It should be clear to the average person skilled in the art that the mentioned (Co-Ce)heterocycloalkyl groups are linked through a carbon atom or a 5p hybridized nitrogen heteroatom. (Cg-Ce)heteroaryl as used herein means furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3- oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1, 2,3-triazinyl, 1,3,5-triazinyl, pyrazoloi|3,4-b|pyridinyl, quinolinyl, pteridinyl, purinyl, 6,7- dihydro-5H-P1|pyridinyl, benzo|bigiophenyl, 5,6, 7,8-tetrahydroquinolin-Z-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphtenyl, isothianaphtenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, etc. It should be understood by one of ordinary skill in the art that said (C 2 -Ce)heteroaryl groups are linked through a carbon atom or p hybridized nitrogen heteroatom, (C 2 -Ce)daryl, when used herein, means phenyl or naphthyl. The compounds of formula (I) may be administered in a pharmaceutically acceptable form either alone or in combination with one or more additional agents that modulate the mammalian immune system or with an anti-inflammatory agent. These agents may include, but are not limited to, cyclosporine A (eg, SandimmunF or Neoralef), paramycin, EC-506 (tacrolimus), leflunomide, deoxyspergualine, mycophenolate (eg, CelceptF)), azathioprine (eg,

ImuranF)), daclizumab (eg, Zenapaxb, OKTZ (eg, OrthoklonFb)), Aibsat, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids (eg, prednisone or dexamethasone). These agents can be prescribed, as part of the same or separate dosage forms, by the same or different routes, according to the same or different prescriptions, according to standard pharmaceutical practice.

The compounds of the present invention include all conformational isomers (for example, cis and trans isomers) and all optical isomers of the compounds of the formula! (eg, enantiomers and diastereomers), also as racemic,

diastereomeric and other mixtures of such isomers. Preferred compounds of formula I include those compounds in which B! is

MAV". Other preferred compounds of formula I include those in which B" is hydrogen, (Ci-Cv)alkyl, (Cg-

Св)alkenyl, (С2-Св)alkynyl, where alkyl, alkenyl and alkynyl groups are optionally substituted by hydroxy, amino, trifluoromethyl, (С:-Св)acyloxy, (С1-Св)alkylamino, ((С1-Св )alkyl)gamino or (C1-Cv)acylamino; or B" is (C3-C10)cycloalkyl, where the cycloalkyl group is optionally substituted with hydroxy, trifluoromethyl or (Ci-

Sv) acyloxy.

Other preferred compounds of formula | include such compounds in which B? is (C3-Ci0)cycloalkyl, where the cycloalkyl group is optionally substituted one to five times by deuterium, hydroxy, trifluoromethyl, halogen, (Ci-Ci)alkyl, hydroxy(Ci-Ci)alkyl, (C1i- Sv)acyl, (C1-Cv)alkylamino(Ci-Cv)acyl, ((Сч1-

Cn)alkyl)gamino(Ci-Cn)dacyl, (Ci-Cn)acylamino, (Ci-Cn)alkoxy-CO-MH, /(Ci-Cn)alkylamino-CO-, (Ci-

Cl)alkenyl, (C2-Cv)alkynyl, halo(Ci-Cv)alkyl, (C1-Cv)acylamino(Ci-Cv)alkyl,

ARV(O)tv M(C1-Cv)alkyl, where t is 0, 1 or 2 and B! and ВЭ are each, independently, chosen from hydrogen or (Си1-

St) alkyl.

Other preferred compounds of formula I include those in which B: and B3 are each independently selected from the group consisting of hydrogen, halogen, (C1-C8)alkyl, (C20-C8)alkenyl, (Co-C8)alkynyl, (Ci-Cv)alkoxy, (Cz-

C10)cycloalkyl, (C3-C10)cycloalkyl, (C1-C1)heterocycloalkyl, (C5-C1)heteroaryl or (C1-C10)aryl.

Especially preferred compounds of formula I include the following compounds: 2-14-Methyl-3-Imethyl-(7H-pyrrolo(2,3-4|Ipyrimidin-4-yl)amino|Icyclohexylpropan-2-ol; 2-I3-(2 -Pdroxyethyl)-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amino|-4-methylcyclohexyl)-propan-2-ol; 2-((5-Isopropenyl-2-methylcyclohexyl)-( 7 H-pyrrolo(|(2,3-4|Ipyrimidin-4-yl)amino|-ethanol; (5-Isopropenyl-2-methylcyclohexyl)-(7 H-pyrrolo|(2,3-4Y|Ipyrimidin-4 -yl)-(2,2,2-trifluoroethyl)amine; 2-14-Methyl-3-((7H-pyrrolo|2,3-d|pyrimidin-4-yl)-(2,2,2- trifluoroethyl)amino|-cyclohexyl)-propan-2-ol; 2-14-Methyl-5-Imethyl-(7H-pyrrolo(2,3-4|Ipyrimidin-4-yl)iamino|cyclohex-3-enylpropan- 2-ol; 2-11-(7H-Pyrrolo(2,3-d|pyrimidin-4-yl)uazetidin-3-yl|Ipropan-2-ol; 2-11-(7H-Pyrrolo(2,3- 4|Ipyrimidin-4-yl)uazetidin-2-yl|Ipropan-2-ol; (5-Fluoro-7H-pyrrolo|2,3-4|pyrimidin-4-yl)-(5-isopropenyl-2-methylcyclohexyl )methyl-amine; 2-I3-((5-Fluoro-7H-pyrrolo(2,3-4|Ipyrimidin-4-ylmethylamino|-4-methylcyclohexyl)-propan-2-ol; (2-Ethyl-4- isopropenylcyclopentyl)methyl-(7H-pyrrolo(2,3-4|pyrimidine-4- il)amine; 2-I3-Ethyl-4-Imethyl-(7H-pyrrolo|(2,3-4|Ipyrimidin-4-ylamino|cyclopentyliupropan-2-ol; 2-I(3-Ethyl-4-(2-hydroxyethyl) -(7H-pyrrolo|2,3-4H|Ipyrimidin-4-ylamino|Hcyclopentyl-propan-2-ol; 2-(2-Ethyl-4-isopropenylcyclopentyl)-(7H-pyrrolo(2,3-4 |pyrimidin-4-thyl)amino|ethanol;(5-(5)-Isopropenyl-2-methylcyclohexyl)methyl-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amine;

3-Methyl-8-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)-8-azabicycloi3.2.1|ocgan-3-ol; 2-I(Icycloheptyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amino|ethanol; 2-(Cyshooctyl-(7H-pyrrolo((2,3-4|pyrimidin-4-yl )amino|ethanol;

Bicyclo(2.2.1|hept-2-ylmethyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)-amine; and 4-Piperidin-1-yl-5-m-tolyl-7H -pyrrolo|(2,3-4|pyrimidine.

The present invention also relates to a pharmaceutical composition for (a) treating or preventing a disease or condition such as organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications caused by diabetes, cancer, asthma, atonic dermatitis, autoimmune diseases thyroid, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases or (b) inhibition of protein tyrosine kinase or Janus kinase C (PIK) in mammals, including humans, containing an effective, for such disease or condition, an amount of a compound of the formula or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition for (a) treating or preventing a disease or condition such as organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications caused by diabetes, cancer, asthma, atopic dermatitis, autoimmune diseases thyroid, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases or (b) inhibition of protein tyrosine kinase or Janus kinase C (PIK) in mammals, including humans, containing an effective, for such disease or condition, an amount of a compound of the formula or a pharmaceutically acceptable salt thereof, alone or in combination with a T-cell immunosuppressant or an anti-inflammatory agent, and a pharmaceutically acceptable carrier.

The present invention also relates to a method of inhibiting protein tyrosine kinase or Janus C kinase (JAKZ) in mammals, including humans, which consists in administering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of treating or preventing a disease or condition such as rejection of transplanted organs, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications caused by diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid diseases, ulcers colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases in mammals, including humans, comprising administering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to treat such condition.

The present invention also relates to a method of inhibiting protein tyrosine kinase or Janus C kinase (PIK) in mammals, including humans, comprising administering to said mammal an effective amount of a compound of formula I! or a pharmaceutically acceptable salt thereof, alone or in combination with a T-cell immunosuppressant or an anti-inflammatory agent.

The present invention also relates to a method of treating or preventing a disease or condition such as rejection of transplanted organs, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications caused by diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis , Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases in mammals, including humans, comprising administering to said mammal an effective amount of a compound of formula | or a pharmaceutically acceptable salt thereof, alone or in combination with a T-cell immunosuppressant or an anti-inflammatory agent.

Detailed description of the invention

The following Reaction Schemes reveal the preparation of the compounds of the present invention. Unless otherwise specified,

B", B, B, and B? in Reaction Schemes and the discussion that follows, such as those indicated above.

SCHEME 1

SI in? with many more

SI in?

Ministry of Health g mm

Kk!

MA to

M 0's and M m

Kk"

MAK where

M and what.

M;

SCHEME 2

SI tr XX ho i 4 mm

Kk and si u

And shU

M M x

Kk g

SI in?

M and mm

KE

Si in? la

M. H. and

SCHEME WITH si

M

M M

In her

M ru XX

Beh M

H

IN

E u si v2 d

Beh M. H

IN

SCHEME 4

Mt

M M

IN

She

4-95

MA at

M

Fe XXII m

IN

;

MA where

M

Fe xx

M

AND

3

HAD to?

M

M M x

IN

SCHEME 5

SI in: p ru HM p

M

Mn;

SI in? the XM stream is still mM

Kk g

OK unit

M x z

M M

SCHEME 6

Si in?

Mt

M

M No. 9

ZK in: re ХМИ ик

In reaction 1 Scheme 1, 4-chloropyrrolo|2,3-d|pyrimidine, a compound of formula HMI was converted to the corresponding compound of formula HMI in which A is benzenesulfonyl or benzyl by treating / HMI with benzenesulfonyl chloride, benzyl chloride or benzyl bromide in the presence of a base such as hydride sodium or potassium carbonate, and a polar aprotic solvent such as dimethylformamide or tetrahydrofuran.

The reaction mixture was stirred at a temperature of from about 0"C to about 70"C, preferably at about 30"C, for a time of about 1 hour to about 3 hours, preferably about 2 hours.

In reaction 2 of Scheme 1, 4-chloropyrrolo|(2,3-d|Ipyrimidine, a compound of the formula HMI was converted into the corresponding 4-aminopyrrolo(2,3-4|Ipyrimidine, a compound of the formula XM) by condensing XMI with an amine of the formula NMV"B". The reaction is carried out in an alcohol, such as tert-butanol, methanol, or ethanol, or another high-boiling solvent, such as dimethylformamide, 1,4-dioxane, or 1,2-dichloroethane, at a temperature of from about 60°C to about 120°C, preferably at about 80°C. Of course, the reaction time is from about 2 hours to about 48 hours, preferably about 16 hours.

In the reaction of Scheme 1, the protecting group was removed from a compound of formula X, in which A is benzenesulfonyl, to give the corresponding compound of formula I, the reaction was carried out by treating XM with a base such as sodium hydroxide or potassium hydroxide, in an alcohol such as methanol or ethanol, or solvent mixtures such as alcohol/tetrahydrofuran or alcohol/water. The reaction was carried out at room temperature for about 15 minutes to about 1 hour, preferably 30 minutes. Removal of the protective group from the compound of formula XU, in which A is benzyl, was carried out by treating XM with sodium in ammonia at a temperature of about -78"C for a time of about 15 minutes to about 1 hour.

In reaction 1, Scheme 2, 4-chloropyrrolo(2,3-4|pyrimidine, a compound of formula XXI, in which A is hydrogen or benzenesulfonate) was converted into 4-chloro-5-halopyrrolo(2,3-4|pyrimidine, a compound of formula XU, in which U is chlorine, bromine, or iodine, the reaction of XXI with M-chlorosuccinimide, M-bromosuccinimide, or M-iodosuccinimide.

The reaction mixture was heated to reflux in chloroform for a time of from about 1 hour to about 3 hours, preferably about 1 hour. Alternatively, in reaction 1 of Scheme 2, 4-chloropyrrolo|2,3-d|pyrimidine of formula XXI, in which A is hydrogen, was converted into the corresponding 4-chloro-5-nitropyrrolo|2,3-d|pyrimidine of formula XX, in which M is nitro, the reaction of XXI with nitric acid in sulfuric acid at a temperature of from about -107°C to about 107°C, preferably at about 0°C, for a time of from about 5 minutes to about 15 minutes, preferably about 10 minutes. A compound of formula XXI, in which Y is nitro, was converted to the corresponding 4-chloro-5-aminopyrrolo(|2,3-si|pyrimidine of formula XX, in which Y is amino, by reaction XXI under conditions well known to one of ordinary skill in the art, such as palladium hydrogenation or stannous chloride (ST) and hydrochloric acid.

In reaction 2 Scheme 2, 4-chloro-5-halopyrrolo|(2,3-4|Ipyrimidine) and the compound of formula XX, in which A is hydrogen, was converted into the corresponding compound of formula XX, in which B? is (C1-Cv)alkyl or benzyl, treated with XX M- butyllithium, at a temperature of about -78"C, and the interaction of the thus obtained dianionic intermediate with an alkyl thallium or a benzyl halide at a temperature from about -78"C to room temperature, preferably at room temperature temperature Alternatively, the dianion thus obtained reacted with molecular oxygen to form the corresponding 4-chloro-5-hydroxypyrrolo(2,3-4|pyrimidine), a compound of formula XIX, in which B: is hydroxy.

A compound of the formula XX, in which U is bromine or iodine and A is benzenesulfonate, was converted into a compound of the formula

XIX, in which B? is (Sev-Sig2)aryl or vinyl, treated with XX M-butyllithium, at a temperature of about -782C, followed by the addition of zinc chloride, at a temperature of about -78"C. The corresponding organozinc intermediate obtained in this way was subjected to interaction with aryl iodide or vinyl iodide in the presence of a catalytic amount of palladium.

In the reaction of Scheme 2, the compound of formula XIX was converted into the corresponding compound of formula XM! processing

XIX with M-butyllithium, lithium diisopropylamine, or sodium hydride, at a temperature of approximately -78°C, in the presence of a polar aprotic solvent such as tetrahydrofuran. The anionic intermediate obtained in this way was reacted with (a) an alkyl halide or benzyl halide, at a temperature of approximately -782°C to room temperature, preferably at -78°C, when BZ is alkyl or benzyl; (p) aldehyde or ketone, at a temperature from about -782C to room temperature, preferably at -78°C, when BZ is alkoxy; and (c) zinc chloride, at a temperature from about -78°C to room temperature, preferably at -787°C, and the corresponding organozinc intermediate thus obtained was reacted with aryl iodide or vinyl iodide in the presence of a catalytic amount of palladium. The resulting reaction mixture was stirred at a temperature from about 50"C to about 80"C, preferably at about 70"C, for a time of about 1 hour to about 3 hours, preferably about 1 hour. Alternatively, the anion thus obtained was reacted with molecular oxygen to form the corresponding 4-chloro-6-hydroxypyrrolo|2,3-4|pyrimidine, a compound of the formula HMI, in which the B is hydroxy.

In reaction 1 Scheme 3, 4-chloropyrrolo(2,3-d|pyrimidine), the compound of formula XXI was converted into the corresponding compound of formula XXII, according to the method described above in reaction C Scheme 2.

In reaction 2 of Scheme 3, the compound of formula XXI! was converted into the corresponding compound of the formula HMI, according to the method described above in reactions 1 and 2, Scheme 3.

In reaction 1 Scheme 4, 4-chloropyrrolo(2,3-4Z|Ipyrimidine, compound of formula XX was transformed into the corresponding 4-aminopyrrolo(2,3-4Z|Ipyrimidine, compound of formula XXIM) according to the method described above in reaction 2 Scheme 1

In reaction 2, Scheme 4, 4-amino-5-halopyrrolo(2,3-d|pyrimidine), a compound of formula XXIM, in which A is benzenesulfonate and 7 is bromine or iodine, was converted into the corresponding compound of formula XXI!

XXIM with (a) arylboronic acid, when B: is aryl, in an aprotic solvent such as tetrahydrofuran or dioxane, in the presence of a catalytic amount of palladium(0), at a temperature of from about 507°C to about 100°C, preferably at about 70 "C, for a time of from about 2 hours to about 48 hours, preferably about 12 hours; (b) alkynes, when BZ: is alkynyl, in the presence of a catalytic amount of copper () and palladium (0) iodide, and a polar solvent such as dimethylformamide, at room temperature, for a time of from about 1 hour to about 5 hours, preferably about 3 hours; and (c) alkenes or styrenes, when B is vinyl or styrenyl, in the presence of a catalytic amount of palladium in dimethylformamide, dioxane, or tetrahydrofuran, at a temperature of about 80"C to about 100C, preferably about 100"C, for a time of about 2 hours to about 48 hours, preferably about 48 hours.

In the reaction of Scheme 4, the compound of formula XXI! was converted into the corresponding compound of the formula ХУ, according to the method described above in reaction C Scheme 2.

In reaction 1, Scheme 5, 4-chloropyrrolo|(2,3d|pyrimidine), a compound of formula XM was converted to the corresponding compound of formula XMI, in which A is as above, according to the procedure described above in reaction 1

Scheme 1.

In reaction 2 Scheme 5, 4-chloropyrrolo(2,3-d|pyrimidine, a compound of the formula XM! was converted into the corresponding compound of the formula XXM by condensing XMI with a compound of the formula VUOH, in the presence of sodium hydroxide. The reaction was carried out in a polar aprotic solvent, such as tetrahydrofuran , and heated under reflux for a time of from about 2 hours to about 4 hours, preferably about 3 hours.

Removal of protective groups was carried out according to the method described above in reaction C Scheme 1.

In reaction 1, Scheme 6, 4-chloropyrrolo|2,3-d|pyrimidine, the compound of formula CHMII was converted to the corresponding compound of formula XXMI by condensing CHMII with the compound of formula 5B2 in the presence of potassium tert-butoxide and in a polar aprotic solvent such as tetrahydrofuran . The resulting reaction mixture was heated under reflux for a time of about 2.5 hours to about 5 hours, preferably about 3.5 hours. A compound of formula XXMI may further be treated with an oxidizing agent well known to one of ordinary skill in the art, such as hydrogen peroxide, ozone, 3-chloroperoxybenzoic acid, or tert-butyl peroxide to provide the corresponding 4-B? sulfinylpyrrole|2,3-9|Ipyrimidine or 4-in sulfonylpyrrole compounds.

The compounds of the presented invention of the basic nature are able to form a wide range of various salts with various inorganic and organic acids. Although such salts should be pharmaceutically acceptable for use in animals, it is also desirable from a practical point of view to first isolate the compounds of the present invention from the reaction mixture in the form of a pharmaceutically unacceptable salt and then simply convert the compound into the free base by treating with an alkaline reagent and further convert the free base into a pharmaceutically acceptable salt. acid additive salt. Acid addition salts of the compounds of the present invention of a basic nature are easily obtained by the interaction of the basic compound with an acceptable equivalent amount of a selected mineral or organic acid in an aqueous medium or an acceptable organic solvent, such as methanol or ethanol. By carefully evaporating the solvent, it is easy to obtain the desired solid salt.

The desired acid salt can also be obtained from a solution of the free base in an organic solvent by adding an acceptable mineral or organic acid to the solution.

Those compounds of the present invention that are acidic in nature are capable of forming basic salts with a variety of pharmaceutically acceptable cations. Examples of such salts are salts of alkali and alkaline earth metals and especially sodium and potassium salts. All such salts are obtained by appropriate methods.

Chemical bases that form non-toxic basic salts with the compounds of the present invention, which are acidic in nature, are used as reagents in the preparation of pharmaceutically acceptable basic salts of the present invention. Such non-toxic basic salts are derivatives of the following pharmaceutically acceptable cations, such as sodium, potassium, calcium, magnesium, etc. These salts can be easily obtained during the interaction of the corresponding acidic compound with an aqueous solution containing the desired pharmaceutically acceptable cation and subsequent evaporation of the resulting solution to dryness, preferably under vacuum. Alternatively, they can also be obtained by mixing a solution of a lower alcohol of an acidic compound and the desired alcoholate of an alkali or alkaline earth metal and then evaporating the resulting solution to dryness under the conditions given above.

In any case, it is preferable to use stoichiometric amounts of the reagent to ensure the complete completion of the reaction and obtain the maximum yield of the desired product.

The compositions of the present invention can be prepared in accordance with generally accepted techniques, using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the present invention can be included in compositions intended for oral, buccal, intranasal, parenteral (for example, intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation. The active compounds of the invention can also be included in formulations with prolonged release.

For oral administration, pharmaceutical compositions can be, for example, tablets or capsules prepared according to generally accepted methods using pharmaceutically acceptable excipients, such as binding agents (for example, pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (for example, lactose, microcrystalline cellulose or calcium phosphate); lubricating agents (for example, magnesium stearate, talc or silicon); disintegrants (for example, potato starch or sodium starch glycolate); or moisturizing agents (eg, sodium lauryl sulfate). Tablets may be coated by methods well known to those skilled in the art. Liquid formulations for oral administration may be, for example, solutions, syrups or suspensions, or they may be dry products for dilution with water or other suitable diluent before use. Such liquid formulations can be prepared using conventional procedures and using pharmaceutically acceptable excipients such as suspending agents (eg, sorbitol syrup, methylcellulose, or hydrogenated edible fats); emulsifiers (for example, lecithin or acacia); non-aqueous solvents (for example, almond oil, fatty esters or ethyl alcohol); and preservatives (eg, methyl or propyl p-hydroxybenzoate or sorbic acid).

For buccal use, the compositions can be tablets or cakes obtained according to the generally accepted method.

The active compounds of the invention can be prescribed for parenteral administration by infusion, which includes the use of conventional methods of catheterization or infusion. Formulations for infusion can be presented in the form of single dosage forms, for example, in the form of ampoules or in the form of multi-dose containers containing preservatives. The compositions may also be suspensions, solutions, or emulsions in an oil or aqueous solvent, and may contain forming agents such as suspending, stabilizing, and/or dispersing agents. Alternatively, the active ingredient may be in the form of a powder for dissolution before use in a suitable solvent, for example, sterile pyrogen-free water.

The active compounds of the invention can also be formulated into rectal compositions such as suppositories or enemas, for example, containing conventional agents such as cocoa butter or other glycerides.

For intranasal or inhalation administration, the active compounds of the invention are preferably delivered in the form of solutions or suspensions from an aerosol can that is extruded or injected into the patient or as an aerosol from an aerosol can or by extrusion using a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a sealed aerosol, a unit dose can be determined using a valve that releases a defined amount. A sealed container or spray can contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for inhalation or insufflation may contain a powdered mixture of the compound of the invention and a suitable powdered filler such as lactose or starch.

The proposed dose of the active compound of the invention for oral, parenteral, or buccal administration to an adult for the treatment of the conditions indicated above (for example, rheumatoid arthritis) is in the range from 0.1 to 1000 mg of the active ingredient per one dose, which can be prescribed, for example, from 1 up to 4 times a day. The aerosol formulation for the treatment of the conditions indicated above (for example, asthma) for an adult is preferably adapted so that each measured dose or "push" of the aerosol contains from 20 mcg to 1000 mcg of the compound of the invention. The full daily dose of the aerosol should be in the range from 0.1mg to 1000mg. It can be prescribed several times a day, for example, 2, 3, 4 or 8 times, taking, for example, 1, 2 or 3 doses each time.

The compounds of formula (I) may be administered in a pharmaceutically acceptable form either alone or in combination with one or more additional agents that modulate the mammalian immune system or with an anti-inflammatory agent. These agents may include, but are not limited to, cyclosporine A (eg,

SandimunF or NeoralF, paramycin, EC-506 (tacrolimus), leflunomide, deoxysperguapine, mycophenolate (eg, CelceptF), azathioprine (eg, ImuranfF), daclizumab (eg, ZenapaxF), OCtTZ (eg, OrthoklonF), AlZat, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids (eg, prednisolone or dexamethasone).These agents may be administered, as part of the same or separate dosage forms, by the same or different routes, under the same or different prescriptions, according to standard pharmaceutical practice.

ECBOb (Tacrolimus) is taken orally at 0.10-0.15 mg/kg of body weight, every 12 hours, except for the first 48 hours after surgery. The level of tacrolimus is monitored by its presence in the serum.

Cyclosporin A (Sandimun in the form of formulations for oral or intravenous administration, or Neoral, oral solutions or capsules) is taken orally at 5 mg/kg of body weight, every 12 hours except for 48 hours after surgery. The level of cyclosporin A is monitored by its presence in the blood.

Active agents can be formulated for sustained release according to methods well known to one of ordinary skill in the art. Examples of such formulations can be found in United States patents

States 3538214, 4060598, 4173626, 3119742 and 3492397.

The ability of the compounds of formula I or their pharmaceutically acceptable salts to inhibit Janus Z kinase and, accordingly, to demonstrate their effectiveness in the treatment of diseases or conditions characterized by Janus Z kinase are further shown in the ip myo studies.

Biological research

CHUAKZ (UNI O5T) Fermentation research

In studies of ZCHAKZ kinase, a protein expressed in bacillovirus-infected 5E9 cells (fusion protein 257 and the catalytic domain of human AKZ) purified by affinity chromatography on glutathione-Sepacharose was used. The substrate for the reaction is poly-glutamic acid-tyrosine (POT (4:11), catalog bZidta Ж РО275), applied to Mips Mahi bogr plates at a concentration of 10 Opg/ml overnight at a temperature of 3776. In the morning after application, the plates were washed three times and ZAKZ was added to cells containing 100 µl of kinase buffer (5X0MM NERE5, pH 7.3, 125mM Mass, 24mM Mds!g), 40.21M ATRAiTMM Ma orthovanadate. The reaction continued for 30 minutes at room temperature and the plates were washed three times. The level of phosphorylated tyrosine in these cells was calculated using the standard EGISA method using an antiphosphotyrosine antibody (CM RU20, cat. 2469-151-1).

OMO Z9/I -4 Cellular studies for AKZ kinase inhibitors

The study of YUOMO Z39/I -4 is aimed at detecting the activity of inhibitors of "AKZ kinase", which is a precursor of immunosuppression and/or allergy. The researchers used a B-cell line called ОМОЗ39, which is part of the luciferase control gene of the embryo line IDE stability promoter integrated into one of the chromosomes. When these cells are stimulated by II-4, the kinase CHAKZ, which is bound to the II-4 receptor, phosphorylates the signal transducer 5TATb. 5TATv then inhibits the embryo line IDE promoter and the start of transcription of the luciferase gene. The content of luciferase is measured in the lysate of these cells using the Rgoted system for the study of luciferase.

Designation: OMOZ39 cells are grown ARMI 1640 supplemented with 1095 pre-inactivated ROB, 2MM I-glutamine, and 10bodynts/ml Rep./5iger. Did the cells grow from 1x10? up to 1x10e2 cells/ml. Destroyed up to 1x105 on Friday, cells were approximately 1x1059 on Monday. Then split 1:2 for a week, keeping 200 ml in a flask as needed.

Хх105 0ОМОЗ39 cells were placed on 100 μl of VRMI 1640 supplemented with 1095 pre-inactivated ROB, 2 mM I-glutamine, and 10 cells/ml Rep./Ziger in a 96-cell Mee bottom plate (Mips). The compounds were serially diluted 1:22 in DMSO starting from 4 mM to 1.9 µM. In 96 cell polypropylene plates, changing ends after each dilution. Then 5 µl of each dilution was added to 500 µl of ARMI/195 serum in a 96 tube rack. 125 μl of diluted compounds were added to the cells and incubated at 37°C, 595°C for an hour.

After an hour, 25 μl of 25 ng/ml I1I-4 was added to the cells and mixed. The final concentration of II -4 was 2.5ng/ml and the final concentration of the compound was from 20µM to 156nM. The cell was left overnight, 16-18 hours. Plates were then centrifuged at 2500-3000 rpm in a centrifuge for 5 minutes. The supernatant containing the culture was carefully separated by suction from 8 cells. 100 μl of PB5 with calcium and magnesium was added to the applied cells.

Cells were resuspended in RV5 and transferred to Raskaga and OriyaRiaye. 100 μl of Raskag's reagent was added to the Origlia cells.

The following examples illustrate the preparation of the compounds of the present invention, but are not limited to its details. Melting points were not corrected. NMR data were indicated in m.ch. (5) and relative to the deuterium signal from the solvent sample (deuterochloroform, unless otherwise specified). Commercial reagents were used without prior purification. The abbreviation THF refers to tetrahydrofuran. The abbreviation DMF refers to. M,M-dimethylformamide. Low Resolution Mass Spectroscopy (NRMS) was taken on or Nemey

Raskaga 5989F) using chemical ionization (ammonia), or Rizop5 (or City Mazkh5) platform Chemical ionization at atmospheric pressure (CHIAT) platform that used a 50/50 mixture of acetonitrile/water with

0.190 formic acid as an ionizing agent. The term room temperature or ambient temperature means 20-2576.

EXAMPLE 1

Cyclohexylmethyl-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amine

METHOD

Cyclohexylmethylamine

To a solution of cyclohexanone (98mg/1mmol) and acetic acid (120mg/2mmol) dissolved in 2.0ml of 1,2-dichloroethane, 2.0ml of a 2M solution of methylamine in methanol was added and the resulting mixture was stirred at room temperature for 4h. Borohydride on a polymer carrier (1g/2.5mmol) was added and the mixture was stirred at room temperature for 1h, then filtered and concentrated to dryness in vacuo to give bbmg (40965) of the title compound as the acetate salt. "H NMR (400 MHz) (COzOO) 5: 1.17-1.37 (m, 5H), 1.67 (shd, 1H, U - 12.5 Hz), 1.83 (shd, 2H, U - 18.7 Hz), 1.86 (s, ZN), 2.04 (shd, 2H, U - 10.2 Hz), 2.60 (s, ZN), 2.86-2.92 (m , 1H).

METHOD B

Cyclohexylmethyl-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amine

A mixture of 200 mg (1.30 mmol) of 4-chloro-7H-pyrrolo|2,3-4|Ipyrimidine (obtained by the Vamoya method), U. At. Spent os, (1960), 82, 131), the product from Method A (589mg/5.21mmol) and 3ml tert-butanol were stirred in a closed flask at 1007С for 24h. The reaction mixture was poured into water, acidified to pH 1 using 1 M CARRIER (water), washed twice with diethyl ether (ether) and basified to pH 14 using 1 M sodium hydroxide (MaoOnH). The resulting residue was filtered and dried in a vacuum to obtain 26 mg (8895) of the title compound, mp 177-1802C. "IN NMR (400 MHz, SOSIz): 5 1.11-1.22 (m, 1H), 1.43-1.63 (m, 4H), 1.73 (shd, 1H, U - 13.3 Gu), 1.83-1.90 (m, 4 N), 3.23 (s, ЗН), 4.69 (w, 1Н), 6.53 (d, 1Н, U - 3.5 Hz) , 7.03 (d, 1H, U - 3.5 Hz), 8.30 (s, 1H), 10.6 (w, 1H). NRMO:231(MA1).

The compounds indicated in the headings of Examples 2-84 were obtained by a method similar to that described in Example 1.

EXAMPLE 2

Benzylethyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amine

Benzylethylamine. Melting point: 170-1727C; NRMS: 252.3.

EXAMPLE Z

Methyl-(5)-1-Phenylethyl)-7H-pyrrolo|2,3-4|pyrimidin-4-yl)amine

Methyl-(5)-1-phenylethylamine. Melting point: 13172; NRMS: 253.

EXAMPLE 4

Cyclopentylmethyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amine

Cyclopentylmethylamine. NRMS: 217.3.

EXAMPLE 5

Allylcyclohexyl-(7H-pyrrolo|(2,3-4|pyrimidin-4-yl)amine

Allylcyclohexylamine. NRMS: 257.

EXAMPLE 6

Allylcyclopentyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amine

Allylcyclopentylamine. Melting point: 173-175"; NRMS: 243.

EXAMPLE 7

Allylcyclopentyl 7H-pyrrolo(|(2,3-4|pyrimidin-4-yl)amine

Cyclohexylethylamine. NRMS: 245.3.

EXAMPLE 8 (1-Cyclohexylethyl)methyl(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amine (1-Cyclohexylethyl)methylamine. NRMS: 259.4.

EXAMPLE 9

Cycloheptylmethyl-(7H-pyrrolo|(2,3-4|pyrimidin-4-yl)amine

Cycloheptylmethylamine. Melting point: 177-1787C; NRMS: 245 3.

EXAMPLE 10

Cyclooctylmethyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amine

Cyclooctylmethylamine. Melting point: 188-1897C; NRMS; 259 4.

EXAMPLE 11

Methyl-(3-methylcyclohexyl)-(7H-pyrrolo|2,3-4Y|Ipyrimidin-4-yl)amine

Methyl-(3-methylcyclohexyl)amine. NRMS: 245.3.

EXAMPLE 12

Methyl-(4-methylcyclohexyl)-(7H-pyrrolo|2,3-4Y|pyrimidin-4-yl)amine

Methyl-(4-methylcyclohexyl)amine. NRMS: 245.3.

EXAMPLE 13

Methyl-(7H-pyrrolo|(2,3-4|pyrimidin-4-yl)-(3,3,5-trimethylcyclohexyl)amine

Methyl-(3,3,5-trimethylcyclohexyl)amine. NRMS: 273.4.

EXAMPLE 14

Cycloheptylethyl-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amine

Cycloheptylethylamine. Melting point: 168-169"; NRMS: 259 4.

EXAMPLE 15

Cyclooctylethyl-(7H-pyrrolo(|(2,3-4|pyrimidin-4-yl)amine

Cyclooctylethylamine. Melting point: 155-156"C; NRMS: 273 4.

EXAMPLE 16 (1-(4-Chlorophenyl)propyl|methyl-(7H-pyrrolo(2,3-4|Ipyrimidin-4-yl)amine (1-(4-Chlorophenyl)propyl|methylamine. HPMS: 301.7.

EXAMPLE 17 (2-(2-Methoxyphenyl)-1-methylethyl|methyl-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amine

(2-(2-Methoxyphenyl)-1-methylethyl|methylamine. HPMS: 297.4.

EXAMPLE 18

Decahydronaphthalen-1-yl)umethyl-(7H-pyrrolo(2,3-4|Ipyrimshin-4-yl)amine

Decahydronaphthalen-1-ylmethylamine. NRMS: 285 4.

EXAMPLE 19

Cyclodecylmethyl-(7H-pyrrolo(|(2,3-4|pyrimidin-4-yl)amine

Cyclopodecylmethylamine. NRMS: 287 1.

EXAMPLE 20

Cyclononylmethyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amine

Cyclononylmethyl. NRMS: 2731,

EXAMPLE 21 2-"(Cyclopentyl-(7H-pyrrolo|(2,3-4Y|Ipyrimidin-4-ylamino|ethanol) 2-Cyclopentylaminoethanol. Melting point: 156-158"; HPMS: 2473.

EXAMPLE 22

Cycloheptyl-(2-methoxyethyl)-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amine

Cycloheptyl-(2-methoxyethyl)amine. NRMS: 289.

EXAMPLE 23

Cycloheptylcyclopropyl-(7H-pyrrolo|(2,3-4Y|pyrimidin-4-yl)amine

Cycloheptylcyclopropylamine. NRMS: 271.4.

EXAMPLE 24

Cycloheptylcyclopropyl-(7H-pyrrolo|(2,3-4H|pyrimidin-4-yl)amino|ethanol

Cyclohexylaminoethanol. Melting point: 200-201 "C; NRMS: 261.3.

EXAMPLE 25

Cyclooctyl-(2-methoxyethyl)-(7H-pyrrolo(2,3-4|Ipyrimshin-4-yl)amine

Cyclooctyl-(2-methoxyethyl)amine. NRMO: 303.

EXAMPLE 26 sec-Butylmethyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amine sec-Butylmethylamine. Melting point: 146-148"C: HPMS: 205.

EXAMPLE 27 2-Methyl-(7H-pyrrolo(2,3-4|Ipyrimidin-4-yl)amino|-phenylpropan-1-ol 2-Methyl-1-phenylpropan-1-ol. HPMS: 283, 265.

EXAMPLE 28 (2-(4-Chlorophenoxy)-1-methylethyl|methyl-(7H-pyrrolo(|2,3-4|pyrimidin-4-yl)amine (2-(4-Chlorophenoxy)-1-methylethyl| methylamine. Melting point: 139-141"; HPMS: 319, 317, 189.

EXAMPLE 29

M-Cyclohexyl-M',M'-dimethyl-M-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)upropane-1,3-diamine

M-Cyclohexyl-M',M'-dimethylpropane-1,3-diamine. NRMS: 302.4.

EXAMPLE 30

M-(2-Diclohexyl-(7H-pyrrolo(2,3-4|Ipyrimidin-4-yl)amino|ethylacetamide)

M-Cyclohexylaminoethylacetamide. NRMS: 302.4.

EXAMPLE 31 2-Cycloheptyl-(7H-pyrrolo(2,3-4|Ipyrimshin-4-yl)amino|ethanol 2-Cyclohexylaminoethanol. Melting point: 69-72"; HPMS: 275.4.

EXAMPLE 32 2-Cyclooctyl-(7H-pyrrolo|(2,3-4H|Ipyrimidin-4-yl)amino|ethanol 2-Cyclooxylaminoethanol. Melting point: 66-77"; HPMS: 289.4.

EXAMPLE 33 (3,p5-Dimethylcyclohexyl)methyl(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amine (3,5-Dimethylcyclohexyl)methylamine. NRMS: 259.4.

EXAMPLE 34 2-I(Benzyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amino|ethanol 2-Benzylaminoethanol. HPMS: 269, 251.

EXAMPLE 35

C3-(Cyclopentyl-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amino|propan-1-ol

Z-Cyclopentylaminopropan-1-ol. Melting point: 162-164"C; NRMS: 261.3.

EXAMPLE 36

C3-(Cycloheptyl-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amino|propan-1-ol

Z-Cycloheptylaminopropan-1-ol. Melting point: 62-66"C; NRMS: 289.4.

EXAMPLE 37 2-(Decahydronaphthalen-2-yl)-(7H-pyrrolo|2,3-4Y|Ipyrimidin-4-yl)amino|ethanol 2-Decahydronaphthalen-2-ylaminoethanol. Melting point: 75"C; NRMS: 315.

EXAMPLE 38 2-(-Ethylpropyl)-(7H-pyrrolo|(2,3-4|pyrimidin-4-yl)amino|ethanol 2-(1-Ethylpropyl)aminoethanol. Melting point: 49-537С; HPMS: 249 ,3.

EXAMPLE 39 1-(Cyclohexyl-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amino|butan-2-ol

Cyclohexylaminobutan-2-ol. NRMS; 289.

EXAMPLE 40

Bicyclo(2,2,1|hept-2-ylmethyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amine)

Bicyclo(2,2,1|hept-2-ylmethylamine. HPMS: 243.

EXAMPLE 41 2(5)-Yacyclohexyl-(7H-pyrrolo|(2,3-4|pyrimidin-4-yl)yaamino|methyl)-cyclohexanol 2-(Cyclohexylamine)umethylcyclohexanol. NRMS: 329.

EXAMPLE 42 2(8)-Yacyclohexyl-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amino|methyl)-cyclohexanol 2-(Cyclohexylamine)umethylcyclohexanol. NRMS: 329.

EXAMPLE 43 (2-Ethylcyclopentyl)methyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amine (2-Ethylcyclopentyl)methyl amine. HPMS: 287.

EXAMPLE 44

Cyclononylmethyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amine

Cyclononylmethylamine. NRMS: 273.

EXAMPLE 45

Methyl-(7H-pyrrolo|(2,3-4|pyrimidin-4-yl)-(2,4,4-trimethylcyclopentyl)amine

Methyl-2,4,4-trimethylcyclopentyl)amine. NRMS: 259.

EXAMPLE 46 (3-Ethylcyclopentyl)methyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amine (3-Ethylcyclopentyl)methylamine. HPMS: 245.

EXAMPLE 47 (2,5-Dimethylcyclohexyl)methyl-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amine (2,5-Dimethylcyclohexyl)methylamine. NRMS: 259.

EXAMPLE 48 (3,4-Dimethylcyclohexyl)methyl-(7H-pyrrolo|(2,3-4|pyrimidin-4-yl)amine (3,4-Dimethylcyclohexyl)methylamine. HPMS: 259.

EXAMPLE 49 (4-Isopropylcyclohexyl)methyl-(7H-pyrrolo(|2,3-4|pyrimidin-4-yl)amine (4-Isopropylcyclohexyl)methylamine. HPMS: 273.

EXAMPLE 50 (Decahydronaphthalene-1-yl)methyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amine (Decahydronaphthalene-1-yl)umethylamine. HPMS: 285.

EXAMPLE 51 (2,2-Dimethylcyclohexyl)methyl-(7H-pyrrolo|(2,3-4|pyrimidin-4-yl)amine (2,2-Dimethylcyclohexyl)methylamine. HPMS: 259.

EXAMPLE 52 (2-Isopropyl-5-methylcyclohexyl)methyl-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amine (2-Isopropyl-5-methylcyclohexyl)methylamine. NRMS: 287.

EXAMPLE 53

Methyl-(3-methylcyclopentyl)-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amino)amine

Methyl-(3-methylcyclopentyl)amine. NRMS: 231.

EXAMPLE 54 (1-Benzylpiperidin-4-yl)methyl-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amine (1-Benzylpiperidin-4-yl)umethylamine. NRMS: 322.

EXAMPLE 55 (4-tert-Butylcyclohexyl)methyl-(7H-pyrrolo|(2,3-4|pyrimidin-4-yl)amine (4-tert-Butylcyclohexyl)methylamine. HPMS: 287.

EXAMPLE 56

Indan-1-ylmethyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amine

Indan-1-ylmethylamine. NRMS: 265.

EXAMPLE 57 (4-Ethyl-cyclohexyl)methyl-(7H-pyrrolo(|(2,3-4|pyrimidin-4-yl)amine (4-Ethylcyclohexyl)methylamine. HPMS: 259.

EXAMPLE 58

Methyl-(7H-pyrrolo(|(2,3-4|pyrimidin-4-yl)-(1,2,3,4-tetrahydrophthalen-2-yl)amine)

Methyl-1,2,3,4-tetrahydronaphthapen-2-yl)amine. NRMS: 279.

EXAMPLE 59

Bicyclo!13.2.1|oct-2-ylmethyl-(7H-pyrrolo(|(2,3-4|pyrimidin-4-yl)amine

Bicyclo!/3.2.1|oct-2-ylmethylamine. NRMS: 257.

EXAMPLE 60

Methyl-(octahydro-4,7-methanoinden-5-yl)-(7H-pyrrolo(2,3-d|pyrimidin-4-yl)amine

Methyl-(octahydro-4,7-methanoinden-5-yl)damine. NRMS: 283.

EXAMPLE 61

Bicyclo(2.2.1|hept-2-ylmethyl-(7H-pyrrolo)|(2,3-4|pyrimidin-4-yl)amine

Bicyclo(2.2.1|hept-2-ylmethylamine. HPMS: 243.

EXAMPLE 62

(5-Chlorindan-1-yl)methyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amine (5-Chlorindan-1-yl)umethylamine. HPMS: 299.

EXAMPLE 63

Adamanthan-2-ylmethyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amine

Adamanthan-2-ylmethylamine. NRMS: 283.

EXAMPLE 64 (Decahydronaphthalen-2-yl)methyl-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amine (Decahydronaphthalen-2-yl)umethylamine. NRMS: 285.

EXAMPLE 65 (3,5-Dimethylcyclohexyl)methyl-(7H-pyrrolo|2,3-4|Ipyrimidin-4-yl)amine (3,5-Dimethylcyclohexyl)methylamine. NRMS: 259.

EXAMPLE 66

Bicycloyl3.3.1 |non-9-ylmethyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amine

Bicycloi3.3.1|non-9-ylmethylamine. NRMS: 271.

EXAMPLE 67 (1-Isopropyl-4-methylbicyclo|3.1.0|hex-3-yl)umethyl-(7H-pyrrolo(|2,3-4|pyrimidin-4-yl)amine (1-Isopropyl-4- methylbicyclo|3.1.0|hex-3-yl)umethylamine, HPMS: 285.

EXAMPLE 68

Cyclobutylmethyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amine

Cyclobutylmethylamine. NRMS: 203.

EXAMPLE 69 (2,2-Dimethylcyclopentyl)methyl-(7H-thyrolo(2,3-4|pyrimidin-4-yl)amine (2,2-Dimethylcyclopentyl)methylamine. HPMS: 245.

EXAMPLE 70 4-IMethyl-(7H-pyrrolo(2,3-4|Ipyrimidin-4-yl)amino|cyclohexanecarboxylic acid ethyl ester 4-(Methylamino)cyclohexanecarboxylic acid. HPMS: 303.

EXAMPLE 71 (2-Isopropyl-5-methylcyclohexyl)methyl-(7H-pyrrolo|(2,3-4|pyrimidin-4-yl)amine (2-Isopropyl-5-methylcyclohexyl)methylamine. HPMS: 287.

EXAMPLE 72 (3,3-Dimethylcyclohexyl)methyl-(7H-pyrrolo|(2,3-4|pyrimidin-4-yl)amine (3,3-Dimethylcyclohexyl)methylamine. HPMS: 259.

EXAMPLE 73 1(5)-(Cyclohexyl-(7H-pyrrolo(2,3-4Y|pyrimidin-4-yl)amino|propan-2-ol) 1-(Cyclohexylamino|propan-2-ol. HPMS: 275 4 .

EXAMPLE 74 1(8)-(Cyclohexyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amino|Ipropan-2-ol) 1-(Cyclohexylamino|propan-2-ol. HPMS: 275 4 .

EXAMPLE 75

3-(Cyclohexyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amino|propane-1,2-diol)

C3-(Cyclohexylamino|propane-1,2-diol. HPMS: 291.4.

EXAMPLE 76 2-(Decahydronaphthalen-1-yl)-(7H-pyrrolo|(2,3-4Z|Ipyrimidin-4-yl)amino|ethanol 2-KDecahydronaphthalen-1-yl)amino|ethanol. NRMS: 315.4.

EXAMPLE 77 (2-Cycloheptyl-(7H-pyrrolo((2,3-4|Ipyrimidin-4-yl)amino|ethylcarbamic acid) tert-butyl ester of 2-K(Cycloheptylamino)ethylcarbamic acid. HPMS: 374.5.

EXAMPLE 78

Methyl-(3-methylcyclohexyl)-(7H-pyrrolo|2,3-4Y|Ipyrimidin-4-yl)amine

Methyl-(3-methylcyclohexyl)amine. NRMS: 359.4.

EXAMPLE 79

Methyl-(2-methylcyclohexyl)-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amine

Methyl-(2-methylcyclohexyl)amine. NRMS: 359.4.

EXAMPLE 80 (2-Ethylcyclohexyl)methyl-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amine (2-Ethylcyclohexyl)methylamine. NRMS: 373 4.

EXAMPLE 81

Methyl-(2-propisocyclohexyl)-(7H-pyrrolo|2,3-4|Ipyrimidin-4-yl)amine

Methyl-(2-propylcyclohexyl)amine. NRMS: 3874.

EXAMPLE 82 (2,4-Dimethylcyclohexyl)methyl-(7H-pyrrolo|(2,3-4|Ipyrimidin-4-yl)amine (2,4-Dimethylcyclohexyl)methylamine. HPMS: 373.4.

EXAMPLE 83

Methyl-(7H-pyrrolo|(2,3-4|pyrimidin-4-yl)-(2,5,5-trimethylcyclohexyl)amine

Methyl-(2,5,5-trimethylcyclohexyl)amine. NRMS: 387.4.

EXAMPLE 84

Methyl-(7H-pyrrolo(|(2,3-4|pyrimidin-4-yl)-(2,2,5,5-tetramethylcyclohexyl)amine)

Methyl-(2,2,5,5-tetramethylcyclohexyl)amine. NRMSO: 401.

EXAMPLE 85

Cyclohexylmethyl-(6-Phenyl-7H-pyrrolo(2,3-4|Ipyrimidin-4-yl)amine

Cyclohexylmethylamine.

METHOD

7-Benzenesulfonyl-4-chloro-7H-pyrrolo|2,3-4Y|Ipyrimidine

In a flame-dried flask in a nitrogen atmosphere containing 780 mg of 6095 sodium hydride (19.5 mmol) in mineral oil, 3 ml of dimethylformamide (DMF) was added and the resulting mixture was cooled to 0"C.

A solution of 2.0 g (13.0 mmol) of 4-chloro-7H-pyrrolo(2,3-d|pyrimidine in 1 Oml) was added slowly over 5 minutes

DMF. The reaction mixture was stirred for another 10 minutes, during which the evolution of hydrogen (Hg) was completed.

Benzenesulfonyl chloride (1.7 ml/13.0 mmol) was added, the reaction mixture was heated to room temperature and stirred for 1 h. Water was added and the resulting residue was filtered and dried in a vacuum to give

Z, Ag (8995) of the compound indicated in the title in the form of a crystalline solid, Tpl. 163-16770.

METHOD

7-Benzenesulfonyl-4-chloro-6-phenyl-7H-pyrrolo|2,3-4Y|Ipyrimidine A flame-dried flask in a nitrogen atmosphere containing 0.5 µml (3.79 mmol) diisopropylamine dissolved in 5 ppm tetrahydrofuran ( THF) was cooled to -78°C. n-butyllithium (3.75 mmol in the form of a 2.5M solution in hexane) was added and the resulting mixture was brought to 0°C with constant stirring for 10 minutes. The reaction mixture was again cooled to -78 70 and to this mixture for 10 min. a solution of 1.0 g (3.40 mmol) of the product from Method C in 10 ml of THF was added. The reaction mixture was stirred for 1 h at -78"C, and then 8.2 ml (4.10 mmol) of a 0.5 M solution of zinc chloride in THF was added, the temperature of the reaction mixture was brought to room temperature and stirred for 1 h. Iodobenzene was added (0.4 bml/ 4.11 mmol) and a suspension of 197 mg of tetrakis(triphenylphosphine)-palladium in 2 ml of THF. The resulting mixture was stirred at boiling for 3 h, cooled to room temperature and partitioned between dichloromethane and water. The aqueous layer was acidified with 1 M HCl and extracted twice with dichloromethane.

The dichloromethane layers were combined, washed with 1 M NOI and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate (Ma5O4), filtered and concentrated in vacuo to obtain the title compound. NRMS: 370, 372 (М--2).

METHOD E

4-Chloro-6-Phenyl-7H-pyrroloH2,3-hyPpyrimidine

The product from Method OO was dissolved in 10 ml of THF and 5.0 ml of methanol and 1.0 g of Mmaon were added to this solution.

The reaction mixture was stirred for 15 min., concentrated in vacuo and partitioned between a saturated aqueous solution of ammonium chloride (AMCl) and ethyl acetate. The resulting aqueous layer was extracted twice with ethyl acetate.

The ethyl acetate layers were combined, washed with a saturated aqueous solution of sodium chloride, dried over Ma5O, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (1:5 ethyl acetate/hexane) to give 0.59 g (7690) of the title compound as a pale yellow solid, mp 14572 (distinction). NRMO: 230, 232 (М--2).

METHOD E

Cyclohexylmothyl(b-phenyl-7H-pyrrolo|2,3-4|pyrimidin-4-yl)amine

The product from Method E (50 mg/0.218 mmol) was reacted with 0.12 mL of M-methylcyclohexylamine (0.920 mmol) as described in Method B. The reaction mixture was concentrated in vacuo, methanol was added, and the resulting residue was filtered to give 7 mg (1095) of the title compound compound as a yellow solid. "H NMR (400 MHz, SOSIz) 6: 1.18-1.25 (m, 1H), 1.47-1.66 (m, 4H), 1.75-1.90 (m, 5H), 3.30 (s, 3H), 4.74 (w, 1H), 6.79 (s, 1H), 7.32-7.36 (m, 1H), 7.47-7.51 (m, 2H), 7.77 (d, 2H, y - 7.9 Hz), 8.33 (s, 1H). NRMSO: 307 (M1).

The compound indicated in the title of Example 86 was obtained by a method similar to that described in Example 85.

EXAMPLE 86 (1H-Indol-5-yl)-(6-phenyl-7H-pyrrolo|2,3-4|pyrimidin-4-yl)amine 1nH-Indolamine. NRMS: 326.4,

EXAMPLE 87

Cyclohexylmethyl-(b-methyl-7H-pyrrolo|2,3-4Y|Ipyrimidin-4-yl)amine

Cyclohexylmethylamine.

METHOD 7-Benzenesulfonyl-4-chloro-6-methyl-7H-pyrrolo|(2,3-4|pyrimidine

0.57 ml (4.07 mmol) of diisopropylamine and 5.0 ml of dry

THF. The solution was cooled to -78"C and 1.6 mL (4.08 mmol) of a 2.5 M solution of n-butyllithium in hexane was added.

The resulting mixture was kept at 0"C and stirred for 10 minutes. After cooling the mixture again to -78"7C, a solution of 1.0g (3.40mmol) of the crude product from Method C in 1Oml of dry THF was added for 10 minutes.

The resulting mixture was stirred for 1 h, then 0.28 ml (4.50 mmol) of iodomethane was added. The reaction mixture was stirred for 2 h, quenched with a saturated solution of MNAeACI and heated to room temperature.

The mixture was stirred for 5 min., diluted with water and extracted three times with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium chloride, dried over Na 2 O, filtered and evaporated in vacuo to give the title compound. NRMS: 308, 310 (M-2).

METHOD N

4-Chloro-6-methyl-7H-pyrrolo|2,3-4|Ipyrimidine

The product from Method (7) was protected as described in Method E. The crude product was purified by trituration with hexane and dichloromethane to give 250 mg (4490) of the title compound as a yellow solid. Mp.

METHODS

Cyclohexylmethyl-(b-methyl-7H-pyrrolo|2,3-4Y|Ipyrimidin-4-yl)amine

The product from Method H (50 mg/0.298 mmol) was reacted with 100 mg (0.883 mmol) of M-methylcyclohexylamine as described in Method B. The reaction mixture was worked up as described in Method B, except that ethyl acetate was used instead of ether. The title compound (42 mg, yield 5895) was obtained as a white solid. Tpl. 221 "C dis. "H NMR (400 MHz, COsiz) 6: 1.15-1.25 (m, 1H), 1.43-1.62 (m, AN), 1.73 (shs, 1H, U - 13.7 Hz), 1.82-1.90 (m, 4H), 2.41 (d, ZN, U - 0.8 Hz), 3.21 (s, ZN) 4.63 (shs , 1H), 6.20 (s, 1H), 8.22 (s, 1H),

10.1 (shs, 1H). NRMSO: 245 (M-n1).

The compound indicated in the title of Example 88 was obtained by a method similar to that described in Example 87.

EXAMPLE 88

Cyclohexyl-(b-methyl-7H-pyrrolo(2,3-4|pyrimidin-4-yl)amine

Cyclohexylamine. NRMS: 231.3.

EXAMPLE 89 4-Cyclohexyloxy-7H-pyrrolo|2,3-4Y|pyrimidine

METHODS. 7-Benzyl-4-chloro-7H-pyrrolo|2,3-4|Ipyrimidine

67 mg (4.89 mmol) of potassium carbonate was added to a stirred solution of 4-chloro-7H-pyrrolo|2,3-4|pyrimidine (250 mg/1.63 mmol) in 1.12 ml of DMF, and the resulting mixture was stirred at room temperature for 20 minutes.

Benzyl chloride (310mg/2.45mmol) was added and the new mixture was stirred at room temperature for 24h, then filtered, concentrated and the residue was purified by chromatography on silica gel (31 hexane/ethyl acetate) to give 318mg (8095) of the title compound. NRMS: 244 1 (M--1).

METHOD M

7-Benzyl-4-cysohexyloxy-7H-pyrrolo|2,3-d|pyrimidine

84 mg (2.10 mmol) of sodium hydride 6095 in mineral oil and 3.0 ml of THF were charged to a flame-dried flask under nitrogen, and the mixture was cooled to 0 °C. Cyclohexanol (0.18 ml/1.70 mmol) was added and the reaction mixture was stirred for 5 min. A solution of 102 mg (0.419 mmol) of the product from Method I in 1.0 ml of THF was added and the mixture was heated under reflux for 3 h. After cooling to room temperature, the reaction mixture was adjusted to pH 1 by adding 2 M carrier and concentrated in vacuo. The resulting residue suspended in ethyl acetate, filtered and the filtrate concentrated in vacuo to give 7 mg (59905) of the title compound as an oil, HPMS: 308 (M--1).

METHOD M

4-cyclohexyloxy-7H-pyrrolo|2,3-4|pyrimidine

33mg (1.433mmol) of sodium was added to liquid ammonia (b,Oml) at -78"C and the resulting dark blue solution was stirred at -787C for 10 minutes. A solution of 75mg (0.244mmol) of the product with

Method M in 3.0 ml of ether. The resulting solution was stirred at -78"C for 1 g, after which it was quenched by adding 500 mg of solid ammonium chloride. After evaporation at room temperature, the solid residue was triturated with 1 ml of ethyl acetate containing 1 ml of acetic acid for 1 g. It was filtered and concentrated in vacuo to obtain crude material. , which was purified by thin-layer chromatography (silica gel; 21 ethyl acetate/hexane) to give 5 mg of the title compound. "H NMR (400 MHz) (SOCI3) 6: 1.27-1.35 (m, bH), 1.62 -1.67 (m, 4H), 5.30-5.36 (m, 1H), 6.55 (d, 1H, y - 3.2 Hz), 7.11 (d, 1H, y - 3 ,2 Hz), 8.37 (she 1H). NRMO: 218.2 (Mat).

EXAMPLE 90

METHOD

4-cyclohexylsulfanyl-7H-pyrrolo|2,3-4|Ipyrimidine

To a solution of 100 mg (0.651 mmol) of 4-chloro-7H-pyrrolo(2,3-d|pyrimidine dissolved in 3.00 ml of THF was added

0.1 Oml (0.818 mmol) of cyclohexyl mercaptan and 100 mg (0.847 mmol) of 9595 potassium tert-butoxide and the resulting mixture was heated under reflux for 3.5 hours. After cooling to room temperature, the reaction mixture was acidified to pH 1 by adding 2M HCl and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1M HCl. The aqueous layer was extracted with ethyl acetate, ethyl acetates! the layers were combined, washed with a saturated aqueous solution of sodium chloride, dried over Ma 5 O", filtered and evaporated in a vacuum.

The crude product was purified by silica gel chromatography (1:3 ethyl acetate/hexane) to give 34 mg (2295) of the title compound as a white solid. Tpl. 162-163. IN NMR (400 MHz) 5: 1.22-1.36 (m, 1H), 1.45-1.64 (m, 5H), 1.75-1.79 (m, 2H), 2.12 -2.14 (m, 2H), 4.18-4.20 (m, 1H), 6.50 (d, 1H, 9U-3.7 Gu), 7.19 (d, 1H,U - 3 .5 Hz), 8.61 (s, 1H), 10.0 (shs, 1H). NRMO:234(MA1).

EXAMPLE 91 5-Chloro-4-piperidin-1-yl-7H-pyrrolo|(2.3-d|pyrimidine

METHOD B

4,5-Dichloro-7H-pyrrolo|2,3-4|pyrimidine 4-Chloro-7H-pyrrolo|(2,3-Y|Ipyrimidine (154 mg, 1.0 mmol) was suspended in b.Oml of dry dichloromethane in dried on flame flask and M-chlorosuccinimide (147 mg, 1.1 mmol) was added to this mixture in one portion.

The resulting mixture was stirred at room temperature for 18 h, after which the solvent was removed under reduced pressure. The residue was triturated with water and isolated by filtration to give 137 mg (7295) of the title compound as a green solid, mp 224-2277C (ext.). NRMOS:188(M1).

METHOD 5

The product from Method B (57mg, 0.3mmol) was suspended in 3.0ml of tert-butanol and piperidine (90ml, 0.9mmol) was added to this solution and the resulting mixture was heated under reflux for 1h. The reaction mixture was cooled to room temperature and water (4.0 ml) was added. The pH of the solution was adjusted to 1 by adding 1 M NOI and then washed with ether. The aqueous layer was removed and the pH was adjusted to 12 by adding 2M Mahon. The solution was extracted with dichloromethane 2x15 ml and the combined organic solutions were washed with water, then with a saturated aqueous solution of sodium chloride and dried over M95O4. Evaporating the solvent gave 45 mg of a yellow solid, which was purified by chromatography on silica gel (3:11 ethyl acetate/hexane) to give 23 Zmg (3295) of the title compound as a light yellow solid. Tpl. 170-1727"S. H NMR (400 MHz, SOSIz) 6: 1.67-1.74 (m, 6H), 3.65-3.67 (m, 4H), 7.10 (s, 1H) , 8.31 (s, 1H). NRMS: 237 (Mn).

The compounds indicated in the headings of Examples 92-94 were obtained by a method similar to that described in Example 91.

EXAMPLE 92 (5-Chloro-7H-pyrrolo|2.3-4Y|Ipyrimidin-4-yl)-(3-ethynylphenyl)amine

Z-Ethynylphenyl)amine. Melting point: 250760.

EXAMPLE 93 (5-Chloro-7H-pyrrolo(2,3-4H|Ipyrimidin-4-yl)ucycloheptylmethylamine

Cycloheptylmethylamine. Melting point: 152-1537C; NRMS: 279.8.

EXAMPLE 94 (5-Chloro-7H-pyrrolo(2,3-4Y|Ipyrimidin-4-yl cyclooctylmethylamine

Cyclooctylmethylamine. Melting point: 151-1537"C; NRMS: 293.8.

EXAMPLE 95 5-Fensch-4-piperidin-1-yl-7H-pyrrolo|2.3-4Y|Ipyrimidine

METHOD T

5-Bromo-4-chloro-7H-pyrrolo|2,3-d|pyrimidine

3.5 g (0.02 mol) of M-bromosuccinamide was added to a stirred solution of 4-chloro-7H-pyrrolo|(2,3-Y|pyrimidine (30 g/0.02 mol) dissolved in 75 ml of chloroform and the resulting mixture was refluxed refrigerator for 1 h. After cooling to room temperature, the residue was removed by filtration and dried under reduced pressure to give 4.1 g (8995) of the title compound. "H NMR (400 MHz) (SOCI3) o: 7.93 (d, 1H, y - 2.8Hz), 8.60 (s, 1H).

METHODS

7-Benzensulfonyl-5-bromo-4-chloro-7H-pyrrolo(2.3-4|pyrimidine

To a suspension of the product from Method T (4.1g/0.018mol) in DMF (15ml) cooled to 0"С, 1.0g (0.025mol) of sodium hydride 6095 in mineral oil was added and the resulting mixture was stirred at 0"С for 15 min.

Benzenesulfonyl chloride (3.2 g/0.018 mol) was added, the reaction mixture was heated to room temperature and stirred for 2 h. Water (15ml) was then added and the resulting solid was filtered off and dried in vacuo to give 5.9g (8995) of the title compound.

METHOD M

7-Benzolsulfonyl-5-bromo-4-piperidin-1-yl-7H-pyrrolo|2.3-d|pyrimidine

A mixture of 2.0 g (5.37 mmol) of the product from Method Ш and 1.1 g (13.4 mmol) of piperidine in 10 ml of tert-butanol was heated at 60"C with stirring for 2 h. After cooling to room temperature, the reaction mixture was partitioned between dichloromethane (25 ml ) and water (25 ml). The dichloromethane layer was dried over sodium sulfate (Mag25054) and concentrated to dryness in vacuo to give 2.2 g (9795) of the title compound. "H NMR (400 MHz) (SOCI3) 6: 1.63 - 1.72 (m, 6H), 3.54-3.57 (m, 4H), 7.53 (t, 2H, U - 2.0 Hz), 7.60 (s, 1H), 7.61 (t, 1H, U - 2.0 Hu), 8.17-8.20 (m, 2H), 8.43 (s, 1H). NRMS: 422.7, 420.7 (Mat).

METHOD M

5-Phenyl-4-piperidin-1-yl-7H-pyrrolo|(2,3-4Y|Ipyrimidine

To a stirred solution of the product from Method M (100mg/0.237mmol) in 1.0ml of dioxane was added 32mg (0.261mmol) of phenylboric acid and 75mg (0.35bmmol) of tribasic potassium phosphate and then 7mg (0.006bmmol) of tetrakistriphenylphosphine)palladium. The resulting mixture was degassed with nitrogen and stirred at 100"C for 48 h. After cooling to room temperature, 1.0 ml of methanol was added, after which 50 mg of Mahon and the new mixture was stirred at room temperature for 1 h. The resulting mixture was partitioned between dichloromethane and water, the dichloromethane layer was dried over Md 5 O 5 and concentrated to dryness in vacuo. The crude product was purified by chromatography on silica gel (2:11 ethyl acetate/hexane) to give 1 mg (2095) of the title compound. H NMR (400 MHz) (SOCI3) 6 : 1.33 -1.34 (m, 4H), 1.43-1.44 (m, 2H), 3.26-3.28 (m, 4H), 7.12 (s, 1H), 7.27 (t , 1H,»9 - 7.2 Hz), 7.38 (t, 2H, U - 8.0 Hz), 7.45 (d, 2H, U - 0.8 Hz), 8.42 (s, 1H). NRMSO: 279.2 (M1).

The compounds indicated in the headings of Examples 96-99 were obtained by a method similar to that described in Example 95.

EXAMPLE 96

Cyclohexylmethyl-(5-Phenyl-7H-pyrrolo|(2,Za|pyrimidin-4-yl)amine

Cyclohexylmethylamine. Melting point: 200"C; NRMS; 307 4.

EXAMPLE 97

Cyclohexyl-|5-(4-fluorophenyl)-7H-pyrrolo|(2,3-4|pyrimidin-4-yl|methylamine

Cyclohexylmethylamine. Melting point: 220"C; NRMS: 325 4.

EXAMPLE 98

Bicyclo(2.2.1 Dhept-2-yl-(5-phenyl-7H-pyrrolo|2,3-4|pyrimidin-4-yl)amine

Bicyclo(2.2.1|hept-2-ylamine. NRMS: 305.4.

EXAMPLE 99

15-(3-Chlorophenyl)-7H-pyrrolo(2,3-4|Ipyrimidin-4-yl|cyclohexylmethylamine

Cyclohexylmethylamine. NRMS: 455.9,

EXAMPLE 100

METHOD X

4-Piperidin-1-yl-7H-pyrrolo(2,3-4|pyrimidine-5-carbonitrile

To a stirred solution of 4-chloro-7H-pyrrolo|2,3-4|Ipyrimidine-5-carbonitrile (54mg/0.Zmmol) (obtained by the method of Tompzep, ei. ai/., U. At. Spet. bos, 1969 , 91, 2102) suspended in 3.0 ml of tert-butanol, piperidine (59 np/0.6 bO0 mmol) was added. The resulting mixture was heated under reflux for 2.5 h and after cooling to room temperature was transferred to a separatory funnel and diluted with ether (20 ml).

The solution was extracted with 2 x 10 ml of 1 M NOI, the combined aqueous layers were adjusted to pH 7 by adding 2 M potassium hydroxide (KOH), and a precipitate formed from the solution, which was collected by filtration, washed with water and dried under reduced pressure to obtain 29 mg (4295) of the title compound in the form colorless solid. Tpl. 209-21170; H NMR (400 MHz) (acetone-sib) 0: 1.72-1.74 (m, 6H), 3.72-3.79 (m, AN), 8.12 (s, 1H), 8, 29 (c1H). NRMS: 228 (MAT).

EXAMPLE 101

METHOD U

4.5 g (0.02 mol) of M-iodosuccinimide was added to a stirred solution of 4-chloro-7H-pyrrolo|(2,3-YAZ|pyrimidine (30 g/0.02 mol) dissolved in 8 b0 ml of chloroform and the resulting mixture was heated under reflux for 1 g. After cooling to room temperature, the residue was filtered off and dried under reduced pressure to give 4.6 g (8295) of the title compound.

METHOD 27 7-Benzenesulfonyl-4-chloro-5-iodo-7H-pyrrolo|(2,3-4|Ipyrimidine

The title compound was prepared as previously described in Method OO using the product from Method

X, obtaining 5.4 g (8095) of material. NRMO: 419.6 (M-n1), 279.7.

METHOD AA

7-Benzenesulfonyl-5-iodo-4-piperidin-1-yl-7H-pyrrolo(2,3-4|pyrimidine

The title compound was prepared as previously described in Method M using the product from Method 2 to give the title compound. NRMS: 469 (M-n1), 329.1.

METHOD VV

7-Benzenesulfonyl-4-piperidin-1-yl-5-triethylsilanylethynyl-7H-pyrrolo|2,3-4Y|Ipyrimidine

211 mg (0.5 mmol) of the product from Method AA, 19 mg (O0.immol) of copper (I) iodide and 58 mg (0.05 mmol) of tetrakis(triphenylphosphine)palladium were loaded into a flame-dried flask under nitrogen. To this mixture was added

About 14 ml (1.00 mmol) of triethylamine and 0.27 ml (1.5 mmol) of triethylsilylacetylene as a solution in 1.5 ml of dry

DMF. The resulting mixture was stirred at room temperature for 3 h, after which 5.0 ml of water was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was dried over Md5Ox and concentrated in vacuo.

The resulting crude product was purified by chromatography on silica gel (7:11 hexane/ethyl acetate) to give 194 mg (8995) of the title compound. NRMS: 481 (М--1), 341.

METHOD SS

5-Ethynyl-4-piperidin-1-yl-7H-pyrrolo|2,3-4|Ipyrimidine

To a stirred solution of the product from Method BB (194mg/0.40mmol) dissolved in 2.0ml of dry THF, 0.4ml (04mmol) of a 1M solution of tetrabutylammonium fluoride in THF was added dropwise. The resulting mixture was stirred at room temperature for 10 minutes. transferred to a methanol solution (3.0 ml) containing 1 g of KOH, the new mixture was stirred at room temperature for 15 min. and concentrated in vacuo.

The residue was separated between water and ethyl acetate, the ethyl acetate layer was washed with water and a saturated aqueous solution of sodium chloride, dried over Mo5O4 and concentrated to dryness under vacuum. The crude product was purified by chromatography on silica gel (2:11 ethyl acetate/hexane) to give 72 mg (64905) of the title compound as a white crystalline substance. Tpl. 179-1812C, "H NMR (400 MHz) (SOCIz) 6: 1.72 (shs, 6H), 3.20 (s, 1H), 3.82-3.83 (m, 4H), 7.47 (s, 1H), 8 35 (s, 1H). NRMS: 227 (Mn).

Claims (12)

1. Derivatives of pyrrolo(2,3-4|Ipyrimidine of the formula: в 2 xx (C Chak n or their pharmaceutically acceptable salt; in which В! is a group of the formula: в? 4 r M U s with vakiyuey, 1 or 2; A " is selected from the group containing hydrogen, (C1-Cv)alkyl, (Co-Cv)alkenyl, (Co-Cv)alkynyl, where alkyl, alkenyl and alkynyl groups are optionally substituted with deuterium, hydroxy, amino, trifluoromethyl , (C1i-Ca)alkoxy, (C1i1-Cv)acyloxy, (C1-Cv)alkylamino, ((C1-Cv)alkyl)gamino, cyano, nitro, (C2-Cv)alkenyl, (C2-Cv)alkynyl or (C1-Cv)acylamino; or P- is (C3-Cio)cycloalkyl, where the cycloalkyl group is optionally substituted with deuterium, hydroxy, amino, trifluoromethyl, (C1-Cv)acyloxy, (C1-Cv)acylamino, ( C1-Cv)alkylamino, ((C1-Cv)alkyl)gamino, cyano, cyano(C1-Cv)alkyl, trifluoromethyl(C1-Cv)alkyl, nitro, nitro(C1-Cv)alkyl or (Ci-Cv)acylamino A is selected from the group consisting of trifluoromethyl(Ci1-Ci)alkyl, (Ci-Ci)alkyldifluoromethylene)(Ci-Ci)alkyl, (Ci-Cio)cycloalkyl, where the cycloalkyl group is optionally substituted from one tofive carboxys, cyano, amino, deuterium, hydroxy, (Ci-Cv)alkyl, (C1-Cv)alkyl, halogen, (C1-Cv)acyl, (C1-Cv)alkylamino, amino(C1-Cv)alkyl , (C1-Cv)alkoxy-CO-MH, (C1-Cv)alkylamino-CO-, (C2-Cv)alkenyl, (C2-Cv)alkynyl, (C1-Cv)alkylamino, amino(C1-Cv)alkyl , hydroxy(C1-Cv)alkyl, (C1-Cv)alkyl(C1-Cv)alkyl, (C1-Cv)acyloxy(C1-Cv)alkyl, nitro, cyano(C1-Cv)alkyl, halogen(C1-Cv) )alkyl, nitro(C1-Cv)alkyl, trifluoromethyl, trifluoromethyl(C1-Cv)alkyl, (C1-Cv)acylamino, (C1-Cv)acylamino(C1-Cv)alkyl, (C1-Cv)alkyl (C1-Cv) Св)acylamino, amino(С1-Св)acyl, amino(С1и-Св)acyl(Си-Св)alkyl, (С1-Св)alkylamino(С1-Св)acyl, ((С1-Св)alkyl)gamino(С1 - C1-acyl, B'5A'9M-CO-O-, B'B'ZM-CO-(C1-C)alkyl, (C1-C)alkyl-5(O)t, B'B'YMO( О)t, B'?B'AM(O) t(Ci-Cv)alkyl, AB(O)tB YAM, VE(O) tv M (C1-Cv)alkyl, where t is 0, 1 or 2 and B"5 and B!E are each, independently, selected from hydrogen or (Ci1-Cv)alkyl; or P: is (C3-C8)cycloalkyl(C1-C8)alkyl, (C1-C8)acyloxy(C1-C8)alkyl, (C2-C8)alkyl(C1-C8)alkyl, piperazinyl(C1-C8)alkyl , (C1-Cv)acylamino(C1-Cv)alkyl, (Cv-Cio)daryl(C1-Cv)alkyl(C1-Cv)alkyl, (C5-Ce)heteroaryl(C1i-Cv)alkoxy(C1-Cv) alkyl, (C1-Cv)alkylthio(C1-Cv)alkyl, (Ce-CiO)arylthio(C1-Cv)alkyl, (Ci-Cv)alkylsulfinyl(C1-Cv)alkyl, (Ce-CiO)darylsulfinyl(C1- C1-Cv)alkyl, (C1-Cv)alkylsulfonyl(C1-Cv)alkyl, (Cv-Cio)arylsulfonyl(Ci-Cv)alkyl, amino(C1-Cv)alkyl, (C1-Cv)alkylamino(C1-Cv)alkyl , (С1-Св)alkyl)gamino, (Сч-Св)alkyl, (С2о-Св)alkenyl, (С2-Св)alkynyl, where alkyl, alkenyl and alkynyl groups are optionally substituted from one to five cyano, nitro, halogen, deuterium, hydroxy, carboxy, (C1-Cv) acylamino, (C1i-Cv) alkoxy (C1-Cv) acylamino, amino (C1-Cv) acyl, (C1-Cv) alkylamino (C1-Cv) )acyl or ((C1-Cv)alkyl)gamino(C1-Cv)acyl; or ER is B13CO(C1-C1)alkyl or AZCO(C3-Sthio)cycloalkyl where BZ is 2200 or EOM where B29 | IN?! each independently selected groups containing hydrogen, deuterium, (C1-Cv)alkyl, (Ce-Cd)aryl(Ci-Cv)alkyl or (C5-Ce)heteroaryl(Ci-Cv)alkyl; or 5 is BY, B''Y(C-C 10)alkyl or K'(C 3 -C 10 )cycloalkyl, where PE" is (C 1 -C 10 )heterocycloalkyl, (C 1 -C 10 )acylpiperazine, (C 1 -C 10 )darylpiperazine, (C5-Ce)heteroarylpiperazine, (C1-Cv)alkylpiperazine, (Cv-C1id)daryl(Ci-Cv)alkylpiperazine, (C5-Coe)heteroaryl(C1-Cv)alkylpiperazine, morpholine, thiomorpholine, piperidine, pyrrolidine, piperidyl, (C1-C1)alkylpiperidinyl, (C1-C10)darylpiperidyl, (C5-C1)heteroarylpiperidyl, (C1-C1)daryl(C1-C1)alkylpiperidyl, (C5-C1)heteroaryl(C1-C1)alkylpiperidyl or (C1- Sv)acylpiperidyl; or 5 is a group of the formula: (sn.), shchi - MMA, ,; in which m/ is 0, 1 or 2; heeb0,1,2 or 3; or 25 is a group of the formula: Ку, (Р) ИИИ (Р), in which 9, P and | each, independently, takes values from 0 to 3; E, K and P each, independently, oxygen, 5(O)a, where there is 0, 1 or 2, ME? or CE"B8; BZ is selected from the group containing hydrogen, (C1-C8)alkyl, trifluoromethyl, trifluoromethyl(C1-C8)alkyl, (C1-C8)alkyldifluoromethylene), (C1-C3)alkyldifluoromethylene)(C1-C3 )alkyl, (C1-Cv)alkoxy(C1-Cv)acyl, (C1-Cv)alkylamino(C1-Cv)acyl, ((C1-Cv)alkyl)gamino(C1-Cv)acyl, (Ce-Cv) aryl, (C5-Ce)heteroaryl, (Cv-Sthio)daryl(C1-Cv)alkyl, (Cv5-Ce)heteroaryl(Ci-Cv)alkyl, (Cv-Sto)daryl(Cv-Cv)aryl, (Cv -Sthio)daryl(C1-C0)aryl(Ci-Cv)alkyl, (C3-Cv)cycloalkyl, (C3-Cv)cycloalkyl(C1-Cv)alkyl, hydroxy(C2-Cv)alkyl, (C1-Cv) acyloxy (C2-Cv) alkyl, (C1-Cv) alkoxy (C2-Cv) alkyl, piperazinyl (Ci-Cv) alkyl, (C1-Cv) acylamino (C1-Cv) alkyl, (Ce-Cio) daryl (C1 -C1-C1-C1-C8)alkyl, (C1-C1-C1)heteroaryl(C1-C1)alkyl, (C1-C1-C1)alkylthio(C1-C1)alkyl, (C1-C1)darylthio( C1-Cv)alkyl, (C1i1-Cv)alkylsulfinyl (Ci-Cv)alkyl, (Cv-Sio)darylsulfinyl (C1-Cv)alkyl, (C1-Cv)alkylsulfonyl (C1-Cv)alkyl, (Ce-Sthio) darylsulfonyl(C1-Cv)alkyl, amino(C1-Cv)alkyl, (Ci-Cv)alkylamino(Ci-Cv)alkyl, ((C1-Cv)alkyl)gamino(C1-Cv)alkyl, ВЕСО( Ci-Cv)alkyl, where ВЗ is Е?OO or 22ОВ2"М, where ВО and В?! each independently selected from the group consisting of hydrogen, (C1-C8)alkyl, (C8-Stoaryl(C1-C8)alkyl or (C8-C8)heteroaryl(C1-C8)alkyl; or BYA(C2-C8) alkyl, where B" is (C1-C8)acylpiperazine, (C1-C8)darylpiperazine, (C5-C8)heteroarylpiperazine, (C1-C8)alkylpiperazine, (C1-C8)daryl(C1i-C8)alkylpiperazine, (C5- Ce)heteroaryl(Ci-Cv)alkylpiperazine, morpholine, thiomorpholine, piperidine, pyrrolidine, piperidyl, (C1i-Cv)alkylpiperidyl, (Cv-Cio)darylpiperidyl, (C5-Ce)heteroarylpiperidyl, (Cv-Stio)daryl(C1- C1-C6)alkylpiperidyl, (C5-C6)heteroaryl(C1-C6)alkylpiperidyl, (C1-C6) alkoxyacyl, (C1-C6)alkylaminoaryl, ((C1-C6)alkyl)aminoacyl or (C1-C6)acylpiperidyl; B" and 28 are each independently selected from the group consisting of hydrogen, (C1-C8)alkyl, amino, hydroxy, (C1-C8)alkyl, (C1-C8)alkylamino, (C1-C8)alkyl)amino, (C1-C8) -Cv)acylamino, (C1i-Cv)acyl (C1-Cv)alkylamino, carboxy, (C1-Cv) alkoxyacyl, (C1-Cv)alkylaminoacyl, ((C1-Cv)alkyl)aminoacyl, aminoacyl, trifluoromethyl, trifluorome tyl(C1-C8)alkyl, (C1-C8)alkyldifluoromethylene), (C1-C3)alkyldifluoromethylene)(C1-C3)alkyl, (C8-C0)aryl, (C5-Ce)heteroaryl, (C8-C8)daryl (Ci-Ci)alkyl, (C5-Ce)heteroaryl(Ci-Ci)alkyl, (Ci-Ci)daryl(Ci-Ci)aryl, (Ci-Ci)daryl(Ci-Stiodaryl(Ci-Ci)alkyl, (C3-Cv)cycloalkyl, (C3-Cv)cycloalkyl(C1-Cv)alkyl, hydroxy(C1-Cv)alkyl, (C1-Cv)acyloxy(C1-Cv)alkyl, (C1-Cv)alkyl (C1-Cv) C1-C8) alkyl, piperazinyl (C1-C8) alkyl, (C1-C8) acylamino (C1-C8) alkyl, piperidyl, (C1-C8) alkylpiperidyl, (C1-C8) daryl (C1-C8) alkoxy (C1-C8) )alkyl, (C5-Ce)heteroaryl(C1-Cv)alkyl (C1-Cv)alkyl, (C1-Cv)alkylthio(C1-Cv)alkyl, (Cv-Cio)darylthio(Ci-Cv)alkyl, (Ci - C1-Cv)alkylsulfinyl(C1-Cv)alkyl, (Cv-Cv)darylsulfinyl(C1-Cv)alkyl, (C1-Cv)alkylsulfonyl(Ci-Cv)alkyl, (Cv-Cv)darylsulfonyl(Ci-Cv)alkyl, amino(C1-Cv)alkyl, (C1-Cv)alkylamino(C1-Cv)alkyl, (C1-Cv)alkyl)gamino(Ci-Cv)alkyl, AZSO(Ci1-Cv)alkyl or B'ZCO(C3- Sto)cycloalkyl, where B!Z is 2200 or 229B2M, where 20 and B?! each independently selected from the group consisting of hydrogen, (C1-C1)alkyl, (C1-C10)aryl(C1-C8)alkyl or (C5-Ce)heteroaryl(C1-C8)alkyl; BH, B'(Ci-C8)alkyl or BH(C3-C8)cycloalkyl, where B" is (C1-C8)acylpiperazine, (C8-C10)arylpiperazine, (C5-Ce)heteroarylpiperazine, (C1- Cn)alkylpiperazine, (Cn-Sio)daryl(Ci-Cn)alkylpiperazine, (C5-Ce)heteroaryl(Ci-Cn)alkylpiperazine, morpholine, thiomorpholine, piperidine, pyrrolidine, piperidyl, (C1-Cn)alkylpiperidyl, (Cn- Cio)darylpiperidyl, (C5-Ce)heteroarylpiperidyl, (Cc-Cio)daryl(C1i-Cv)alkylpiperidyl, (C5-Co)heteroaryl(Ci-Cv)alkylpiperidyl or (Cc1-Cv)acylpiperidyl; or groups of the formula: (c ) I love her (CH) 7 where 0, 1, 2 or 3; and 7 is hydroxy, (C1-1-C8)alkyl or ME'B2, where B! and 22 each independently selected from the group consisting of hydrogen, (C1-C8)alkyl, piperidyl, (C1-C8)alkylpiperidyl, (C8-C8)darylpiperidyl, (C5-C8)heteroarylpiperidyl, (C8-C1iodaryl(C1 - Cn)alkylpiperidyl, (C5-Ce)heteroaryl(C1-Cn)alkylpiperidyl, (C1-Cn)acylpiperidyl, (Cn-Cto)aryl, (C5-Ce)heteroaryl, (Cn-Sthio)aryl(C1-Cn) alkyl, (C5-Ce)heteroaryl(C1-Cv)alkyl, (Cv-Sto)daryl(Cv-Cv)aryl, (Cv-Sthio)daryl(Cv-Cv)daryl(Ci-Cv)alkyl, (Cv- C 1 -cycloalkyl, (C 3 -C )cycloalkyl (C 1 -C )alkyl, C 1 -C 5 alkyl, (C 1 -C 5 )alkyl(SNEZ)(C 1 -C )alkyl, where P is hydroxy, (C 1 -C 5 ) )acyloxy, (C1-C8)alkyloxy, piperazine, (C1-C8)acylamino, (C1-C8)alkylthio, (C1-C8)arylthio, (C1-C8)alkylsulfinyl, (C1-C8)darylsulfinyl, (C1-C8) C1-C1)alkylsulfoxyl, (C1-C10)darylsulfoxyl, amino, (C1-C1)alkylamino, ((C1-C1)alkyl)gamino, (C1-C1)acylpiperazine, (C1-C1)alkylpiperazine, (C1-C1ide)) aryl(Ci-Cv)alkylpiperazine, (Ci-Ce)heteroaryl(Ci1-Cv)alkylpiperazine, morpholine, thiomorpholine, piperidine or pyrrolidine; B5(C1-Cv)alkyl, (C1-Cv)alkyl(SNEU)(Ci-Cv)alkyl, where P: is piperidyl, (Ci-Cv)alkylpiperidyl, (Cv-Cv)darylpiperidyl, (Cv-Cv)aryl (Ci-Cv)alkylpiperidyl, (C5-Ce)heteroarylpiperidyl or (C5-Ce)heteroaryl(C1-Cv)alkylpiperidyl; or E! is there an OB? or 5(0)92U, grandfather, 1 or 2; and A? is selected from the group consisting of trifluoromethyl (Ci1-Ci)alkyl, (Ci-Ci)alkyldifluoromethylene)(Ci-Ci)alkyl, (Ci-Cio)cycloalkyl, where the cycloalkyl group is optionally substituted from one to five carboxy, cyano, amino, hydroxy, (C 1 -C 8 ) alkoxy, halogen, (C 1 -C 8 )alkyl (O) t, where t is 0, 1 or 2; В'ХХЯМ(5) t, where t is 0, 1 or 2 and Kz is each, independently, selected from the group containing hydrogen or (C1-C8)alkyl; (C1-C8)acyl, ( C1-Cv)alkylamino, amino(C1-Cv)alkyl, (C1-Cv)alkoxy-CO-MH, (C1-Cv)alkylamino-CO-, В'ЯВ'ЯМ-CO-0-, В'ЕВ' M-CO-(C1-C1)alkyl, where B" and B" are as indicated above; (C2-Cv)alkenyl, (C2-Cv)alkynyl, (C1-Cv)alkylamino, amino(C1-Cv)alkyl, hydroxy(C1-Cv)alkyl, (C1-Cv)alkyl (C1-Cv)alkyl, (Сч1-Св)acyloxy(С1-Св)alkyl, nitro, cyano(Си-Св)alkyl, nitro(С1-Св)alkyl, trifluoromethyl, trifluoromethyl(Си-Св)alkyl, (Си-Св)acylamino, (С1 -C1-Cv) alkoxy(C1-Cv) acylamino, amino(C1-Cv) acyl, (Ci-Cv) alkylamino(C1-Cv) acyl or ((C1-Cv) alkyl) gamino(C1-Cv) acyl; (C2-Cv)alkenyl, (C2-Cv)alkynyl, (C3-C10)cycloalkyl(Ci-Cv)alkyl, (C1-Cv)acyloxy(C1-Cv)alkyl, (C1-Cv) alkoxy(C1-Cv) )alkyl, piperazinyl(C1-Cv)alkyl, (C1-Cv)dacylamino(C1i-Cv)alkyl, (Ce-C0)daryl(Ci-Cv)alkyl(C1i-Cv)alkyl, (C5-Ce)heteroaryl( C1-Cv)Alkoxy(C1-Cv)alkyl, (C1-Cv)alkylthio(C1-Cv)alkyl, (Cv-Cv)darylthio(Ci-Cv)alkyl, (C1-Cv)alkylsulfinyl(C1-Cv)alkyl , (Cv-Cv)darylsulfonyl(C1-Cv)alkyl, (C1-Cv)alkylsulfonyl(Cv-Cv)alkyl, (Cv-Cv)darylsulfonyl(Cv-Cv)alkyl, amino(C1-Cv)alkyl, (C1 -Cv)alkylamino(C1-Cv)alkyl, ((Ci-Cv)alkyl)gamino, (C1-Cv)alkyl, where the alkyl group is optionally substituted by one to five cyano, nitro, hydroxy, carboxy , (C1-Cv)acylamino, (C1-Cv)alkoxy(C1-Cv)acylamino, amino(C1-Cv)acyl, (C1-Cv)alkylamino(C1i-Cv)acyl or ((C1-Cv)alkyl) gamino(Ci-Cv)acyl; AZSO(Ci1-C8)alkyl or B'3CO(C3-C0)cycloalkyl, where B!Z is 2200 or 229B2M, where 20 and B?! each independently selected from the group consisting of hydrogen, (C1-C8)alkyl, (C1-C8)aryl(C1-C8)alkyl or (C5-Ce)heteroaryl(C1-C8)alkyl; ВЯ, B'(Ci-Cv)alkyl or B(C3-Cio)cycloalkyl, where B" is (Co-Ce)heterocycloalkyl, (C1-Cv)acylpiperazine, (Cv-Cio)darylpiperazine, (C5-Ce) heteroarylpiperazine, (C1-Cv)alkylpiperazine, (Cv-Cio)daryl(C1i-Cv)alkylpiperazine, (C5-Ce)heteroaryl(Ci-Cv)alkylpiperazine, morpholine, thiomorpholine, piperidine, pyrrolidine, piperidyl, (C1-Cv) alkylpiperidinyl, (C1-C1)darylpiperidyl, (C5-C1)heteroarylpiperidyl, (C1-C1)daryl(C1-C1)alkylpiperidyl, (C5-C1)heteroaryl(C1-C1)alkylpiperidyl or (C1-C1)acylpiperidyl; or P? is a group of the formula: Yur (P) Y (P), in which 9, P and | each, independently, takes values from 0 to 6; E, K, and P are each, independently, oxygen, 5(O)4, where a is 0, 1, or 2, ME? or SV'"VU, where R, B" and RZ are as indicated above; B2 and C are each independently selected from the group containing hydrogen, deuterium, amino, halogen, hydroxy, nitro, carboxy, (C2-Cv)alkenyl, (C2-Cv)alkynyl, trifluoromethyl, trifluoromethoxy, (C1-Cv) alkyl, (C1-Cv)alkyl, where alkyl or alkyl groups are optionally substituted by one to three groups selected from halogen, hydroxy, carboxy, amino(C1-Cv)alkylthio, (C1-Cv)alkylamino, ((C1-C6)alkyl)gamino, (C5-C6)heteroaryl, (C2-C6)heterocycloalkyl, (C3-C6)cycloalkyl or (C6-C6)aryl; or P: and C each, independently, (C3-C10)cycloalkyl, (C3-C10)ucycloalkyloxy, (C1-C8)alkylamino, ((C1-C8)alkyl)amino, (C1-C8)darylamino, (C1- C1-C10)alkylthio, (C1-C10)darylthio, (C1-C10)alkylsulfinyl, (C1-C10))darylsulfinyl, (C1-C10)alkylsulfonyl, (C1-C10)darylsulfonyl, (C1-C1)acyl, (C1- C1-C8-C0-MH-, (C1-C8) alkylamino-CO-, (C8-Ce)heteroaryl, (C2-Ce)heterocycloalkyl or (C8-C10)aryl, where heteroaryl, heterocycloalkyl and aryl groups are optional necessarily, substituted one to three times by halogen, (C1-Cv)alkyl, (C1-Cv)alkyl-FO-MH-, (C1-Cv)daloxy-CO-MH-, (C1-Cv)alkyl-CO- МН-(Си-Св)alkyl, (С1-Св)Alkoxy-СО-МН-(С1-Св)alkyl, (С1-Св)Alkoxy-СО-МН-(С1-Св)Alkoxy, carboxy, carboxy(С1) -Cv)alkyl, carboxy(C1-Cv) alkoxy, benzyloxycarbonyl(C1-Cv) alkoxy, (C1-Cv) alkoxycarbonyl(C1-Cv) alkoxy, (Cv-Cv) daryl, amino, amino(C1-Cv) alkyl , (C1-Cv) alkoxycarbonylamino, (Cv-C1id))daryl(C1-Cv)alkylcarbonylamino, (C1-Cv)alkylamino, ((C1-Cv)alkyl)gamino, (Ci-Cv)alkylamino(C1-Cv) alkyl, (Sh1 - C1-Cv)alkyl)gamino(C1-Cv)alkyl, hydroxy, (C1-Cv)alkyl, carboxy, carboxy(C1-Cv)alkyl, (C1-Cv)alkyloxycarbonyl, (C1-Cv)alkyloxycarbonyl(C1-Cv) alkyl, (C1-Cv) alkoxy-CO-MH-, (C1-Cv) alkyl-CO-MH-, cyano, (C5-Ce) heterocycloalkyl, amino-CO-MH-, (C1-Cv) alkylamino-CO -MH-, (C1-Cv)alkyl)gamino-CO-MH-, (Ce-Co)darylamino-CO-MH-, (Cv-Ce)heteroarylamino-CO-MH-, (C1-Cv)alkylamino-SU -MH-(C1-Cv)alkyl, (C1-Cv)alkyl)gamino-CCO-MH-(C1-Cv)alkyl, (Cv-Cio)darylamino-CO-MH-(C1-Cv)alkyl, (C5 -Ce)heteroarylamino-CO-MH-(C1-Cv)alkyl, (C1-Cv)alkylsulfonyl, (C1-Cv)alkylsulfonylamine, (C1-Cv)alkylsulfonylamino(Ci-Cv)alkyl, (Ce-Siodarylsulfonyl, (Cv - Cio)arylsulfonylamine, (C1-C8)arylsulfonylamino(C1-C8)alkyl, (C1-C8)alkylsulfonylamine, (C1-C8)alkylsulfonylamino(C1-C8)alkyl, (C5-Ce)heteroaryl or (C2-Coe) heterocycloalkyl; provided that when one of P and 25 is hydrogen, the other P" or E? cannot be (C 1 -C 10 )aryl or (C 1 -C 10 )aryl(C 1 -C 1 )alkyl; provided that when P" is hydrogen, unsubstituted (C1-C8) alkyl or unsubstituted (C3-C8) cycloalkyl, PE? cannot be (C1-C10)daryl(C1-C1)alkyl; 29th B?! cannot be (C5-C0)heteroaryl(C1-C8)alkyl; and KE!" cannot be (Ce2-Ce)heterocycloalkyl, morpholine, thiomorpholine, piperidine, pyrrolidine, piperidinyl or (C1-Cv)alkylpiperidinyl; provided that the 5p-: and z carbons of alkenyl or alkynyl cannot be substituted by hydroxy or amino group; provided that when KE" is hydrogen, KE? cannot be amino(C1-Cv)alkyl, (C1-Cv)alkyl, (C1-Cv)alkylamino(C1-Cv)alkyl, (C1-Cv)alkyl)gamino(C1-Cv)alkyl, furanyl, (C1 - C1-C1-C8-alkyl or C1-C1-C8-alkyl; provided that P" and 25 cannot both be hydroxy(C1-C8)alkyl; provided that when P is (C1-C8)alkyl, EZ cannot be (C1-C8)hydroxy(C1-C8)alkyl or carboxy(C1-C8)alkyl; and provided that EC cannot be carboxy(C1-C8)alkylthio or (C1-C8)alkoxycarbonyl(C1-C8)alkylthio. 2. Compound according to point 1, in which B' is MVV". 3. The compound according to item 1, in which "PE" is hydrogen, (C1-Cv)alkyl, (C2-Cv)alkenyl, (C2-Cv)alkynyl, where alkyl, alkenyl and alkynyl groups are optionally substituted hydroxy , amino, trifluoromethyl, (C1-C8)acyloxy, (C1-C8)alkylamino, (C1-C8)alkyl)amino or (C1-C8)acylamino; or P is (C3-C8)cycloalkyl, where the cycloalkyl group is necessarily, substituted by hydroxy, trifluoromethyl or (C1-C) acyloxy. 4. The compound according to point 1, in which P? is (C3-C10)cycloalkyl, wherein the cycloalkyl group is optionally substituted one to five times by deuterium, hydroxy, trifluoromethyl, halogen, (C1-C8)alkyl, hydroxy(C1i-C8)alkyl, (C1- C1-Cv)acyl, (C1-Cv)alkylamino(C1-Cv)acyl, ((C1-Cv)alkyl)gamino(C1-Cv)acyl, (C1-Cv)acylamino, (C1-Cv)alkyl-CO-MH , (Ci-Cv)alkylamino-CO-, (Cg-Cv)alkenyl, (C2-Cv)alkynyl, halo(C1-Cv)alkyl, (C1-Cv)acylamino(C1-Cv)alkyl, AR(O) tv YAM, VB(O) and A M(Ci-Cv)alkyl, where t is 0, 1 or 2 and B": and B!E are each independently selected from hydrogen or (C1-Cv)alkyl. 5. The compound according to item 1, in which P2 and C are each independently selected from the group containing hydrogen, halogen, (C1-C8)alkyl, (C2-C8)alkenyl, (Co-C8)alkynyl, (C1 -C 10 -C 100 alkoxy, (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyl, (C 1 -C 10 )heterocycloalkyl, (C 5 -C 10 )heteroaryl or (C 1 -C 10 )aryl. 6. The compound according to point 1, where said compound is selected from the group containing: 2-(4-methyl-3-methyl-(7H-pyrrolo(|2,3-4|Ipyrimidin-4-ylamino|1-cyclohexyl)-propane) -2-ol; 2-I3-(2-hydroxyethyl)-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amino|-4-methylcyclohexyl)propan-2-ol; 2-M( (5-isopropenyl-2-methylcyclohexyl)-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)amino|ethanol; (5-isopropenyl-2-methylcyclohexyl)-(7H-pyrrolo(2, 3-4|pyrimidin-4-yl)-(2,2,2-trifluoroethyl)amine; 2- and 4-methyl-3-K(7H-pyrrolo(2,3-4|pyrimidin-4-yl)-( 2,2,2-trifluoroethyl)amino|cyclohexylpropan-2-ol; 2-(4-methyl-5-Imethyl-(7H-pyrrolo(|(2,3-4|Ipyrimidin-4-ylamino|Ycyclohex-3- enylpropan-2-ol; 2-Y-(7H-pyrrolo|2,3-4|pyrimidin-4-yl)azetidin-3-yl|propan-2-ol; 2-Y-(7H-pyrrolo|2, 3-4|pyrimidin-4-yl)azetidin-2-yl|propan-2-ol; (5-fluoro-7H-pyrrolo(|2,3-4|pyrimidin-4-yl)-(5-isopropenyl- 2-methylcyclohexyl)methylamine; 2-I3-((5-fluoro-7H-pyrrolo|2,3-4|pyrimidin-4-yl)umethylamino|-4-methylcyclohexylpropan-2-ol; (2-ethyl-4- isopropenylcyclopentyl)methyl-(7H-pyrrolo(2,3-4|pyrimidine-4 -yl)amine; 2-(3-ethyl-4-(methyl-(7H-pyrrolo(2,3-4a|Ipyrimidin-4-ylamino|1cyclopentyl)propan-2-ol; 2-(3-ethyl-4-|(2- hydroxyethyl)-(7H-pyrrolo(2,3-4|pyrimidin-4-ylamino|1cyclopentyl)propan-2-ol; 2-M(2-ethyl-4-isopropenylcyclopentyl)-(7H-pyrrolo(|(2 ,3-4|Ipyrimidin-4-yl)amino|ethanol; (5-(5)-isopropenyl-2-methylcyclohexyl)methyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amine; 3-methyl-8-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)-8-azabicycloyl3.2.1|octan-3-ol; 2-(cycloheptyl-(7H-pyrrolo|2,3- 4|pyrimidin-4-yl)amino|ethanol; 2-(cyclooctyl-(7H-pyrrolo(2,3-4|pyrimidin-4-yl)amino|ethanol; bicyclo(2.2.1|hept-2-ylmethyl- (7H-pyrrolo((2,3-4|pyrimidin-4-yl)amine; and 4-piperidin-1-yl-5-m-tolyl-7H-pyrrolo|2,3-4|pyrimidine. 7. A pharmaceutical composition for (a) treating or preventing a disease or condition such as organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications caused by diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disease glands, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases or (b) inhibition of protein tyrosine kinase or Janus kinase C (AKZ) in mammals, including humans, containing an effective amount of the compound according to clause 1 or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier. 8. A pharmaceutical composition for (a) treating or preventing a disease or condition such as organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications caused by diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disease , ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases or (b) inhibition of protein tyrosine kinase or Janus kinase C (AKZ) in mammals, including humans, containing an effective amount of the compound according to clause 1 for such disease or condition or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional agents that modulate the mammalian immune system or anti-inflammatory agents, and a pharmaceutically acceptable carrier. 9. A method of inhibiting protein tyrosine kinase or Janus Z kinase (JKK) in mammals, including humans, wherein said mammal is administered an effective amount of the compound according to item 1 or a pharmaceutically acceptable salt thereof. 10. A method of treatment or prevention of a disease or condition such as rejection of transplanted organs, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications caused by diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid diseases, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases in mammals, including humans, in which said mammal is administered an effective amount of the compound according to item 1 or a pharmaceutically acceptable salt thereof to treat such condition. 11. A method of inhibiting protein tyrosine kinase or Janus kinase C (AKZ) in a mammal, including a human, wherein said mammal is administered an effective amount of a compound according to item 1 or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional agents that modulate the immune system of a mammal, or anti-inflammatory agents. 12. A method of treatment or prevention of a disease or condition such as rejection of transplanted organs, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications caused by diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid diseases, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases in mammals, including humans, in which said mammal is administered an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional agents that modulate the immune system of the mammal, or anti-inflammatory agents.